Energetic modulation of nerves

ABSTRACT

A method to apply a nerve inhibiting cloud surrounding a blood vessel includes creating a treatment plan, wherein the treatment plan prescribes application of the nerve inhibiting cloud towards at least a majority portion of a circumference of a blood vessel wall, and applying the nerve inhibiting cloud towards the majority portion of the circumference of the blood vessel wall for a time sufficient to inhibit a function of a nerve that surrounds the blood vessel wall.

RELATED APPLICATION DATA

This application is a continuation-in-part of U.S. patent applicationSer. No. 12/902,133 filed Oct. 11, 2010, which claims priority to andthe benefit of U.S. Provisional patent application 61/377,908 filed Aug.27, 2010, now pending, and U.S. Provisional patent application61/347,375 filed May 21, 2010, now pending, and is acontinuation-in-part of U.S. patent application Ser. No. 12/725,450filed Mar. 16, 2010, now pending, which is a continuation-in-part ofU.S. patent application Ser. No. 12/685,655, filed on Jan. 11, 2010, nowpending, which claims priority to and the benefit of U.S. ProvisionalPatent Application No. 61/256,983 filed Oct. 31, 2009, now lapsed, U.S.Provisional Patent Application No. 61/250,857 filed Oct. 12, 2009, nowlapsed, U.S. Provisional Patent Application No. 61/261,741 filed Nov.16, 2009, now lapsed, and U.S. Provisional Patent Application No.61/291,359 filed Dec. 30, 2009, now lapsed.

U.S. patent application Ser. No. 12/725,450 also claims priority to, andthe benefit of U.S. Provisional Patent Application No. 61/303,307 filedFeb. 10, 2010, now lapsed, U.S. Provisional Patent Application No.61/256,983 filed Oct. 31, 2009, now lapsed, U.S. Provisional PatentApplication No. 61/250,857 filed Oct. 12, 2009, now lapsed, U.S.Provisional Patent Application No. 61/261,741 filed Nov. 16, 2009, nowlapsed, and U.S. Provisional Patent Application No. 61/291,359 filedDec. 30, 2009, now lapsed.

The disclosures of all of the above referenced applications areexpressly incorporated by reference herein.

This application is related to U.S. patent application Ser. Nos. ______,______, and ______, all entitled “Energetic modulation of nerves”, andhaving respective attorney docket Nos. KM-003-US-CIP1, KM-003-US-CIP2,and KM-003-US-CIP4, filed concurrently with this application.

The following patent applications are also expressly incorporated byreference herein.

U.S. patent application Ser. Nos. 11/583,569, 12/762,938, 11/583,656,12/247,969, 10/633,726, 09/721,526, 10/780,405, 09/747,310, 12/202,195,11/619,996, 09/696,076, 11/016,701, 12/887,178, 12/390,975, 12/887,178,12/887,211, 12/887,232, 11/583,656.

It should be noted that the subject matters of the above applicationsand any other applications referenced herein are expressly incorporatedinto this application as if they are expressly recited in thisapplication. Thus, in the instance where the references are notspecifically labeled as “incorporated by reference” in this application,they are in fact deemed described in this application.

BACKGROUND

Energy delivery from a distance involves transmission of energy waves toaffect a target at a distance. It allows for more efficient delivery ofenergy to targets and a greater cost efficiency and technologicflexibility on the generating side. For example, cellular phones receivetargets from towers close to the user and the towers communicate withone another over a long range; this way, the cell phones can be lowpowered and communicate over a relatively small range yet the networkcan quickly communicate across the world. Similarly, electricitydistribution from large generation stations to the users is moreefficient than the users themselves looking for solutions.

In terms of treating a patient, delivering energy over a distanceaffords great advantages as far as targeting accuracy, technologicflexibility, and importantly, limited invasiveness into the patient. Ina simple form, laparoscopic surgery has replaced much of the previousopen surgical procedures and lead to creation of new procedures anddevices as well as a more efficient procedural flow for diseasetreatment. Laparoscopic tools deliver the surgeon's energy to thetissues of the patient from a distance and results in improved imagingof the region being treated as well as the ability for many surgeons tovisualize the region at the same time.

Perhaps the most important aspect is the fact that patients have muchless pain, fewer complications, and the overall costs of the proceduresare lower. Visualization is improved as is the ability to perform tasksrelative to the visualization.

Continued advances in computing, miniaturization and economization ofenergy delivery technologies, and improved imaging will lead to stillgreater opportunities to apply energy from a distance into the patientand treat disease.

SUMMARY

In some embodiments, procedures and devices are provided, which advancethe art of medical procedures involving transmitted energy to treatdisease. The procedures and devices follow along the lines of: 1)transmitting energy to produce an effect in a patient from a distance;2) allowing for improved imaging or targeting at the site of treatment;3) creating efficiencies through utilization of larger and more powerfuldevices from a position of distance from or within the patient asopposed to attempting to be directly in contact with the target as asurgeon, interventional cardiologist or radiologist might do. In manycases, advanced visualization and localization tools are utilized aswell.

In accordance with some embodiments, a system for treatment includes afocused ultrasound energy source for placement outside a patient,wherein the focused ultrasound energy source is configured to deliverultrasound energy towards a blood vessel with a surrounding nerve thatis a part of an autonomic nervous system inside the patient, and whereinthe focused ultrasound energy source is configured to deliver theultrasound energy from outside the patient to the nerve located insidethe patient to treat the nerve.

In any of the embodiments described herein, the focused ultrasoundenergy source comprises a transducer, and a angle of the focusedultrasound source is anywhere between 30 degrees to 80 degrees withrespect to a line traveling down a center of the transducer relative toa line connecting the transducer to the blood vessel.

In any of the embodiments described herein, the focused ultrasoundenergy source is configured to provide the ultrasound energy to achievepartial ablation of the nerve.

In any of the embodiments described herein, the focused ultrasoundenergy source is configured to deliver the ultrasound energy to thenerve from multiple directions outside the patient while the focusedultrasound energy source is stationary relative to the patient.

In any of the embodiments described herein, the system further includesan imaging processor for determining a position of the blood vessel.

In any of the embodiments described herein, the imaging processorcomprises a CT device, a MRI device, a thermography device, an infraredimaging device, an optical coherence tomography device, a photoacousticimaging device, a PET imaging device, a SPECT imaging device, or anultrasound device.

In any of the embodiments described herein, the processor is configuredto operate the focused ultrasound energy source to target the nerve thatsurrounds the blood vessel during the ultrasound energy delivery basedon the determined position.

In any of the embodiments described herein, the processor is configuredto determine the position using a Doppler triangulation technique.

In any of the embodiments described herein, the focused ultrasoundenergy source is configured to deliver the ultrasound energy having anenergy level sufficient to decrease a sympathetic stimulus to thekidney, decrease an afferent signal from the kidney to an autonomicnervous system, or both.

In any of the embodiments described herein, the focused ultrasoundenergy source has an orientation so that the focused ultrasound energysource aims at a direction that aligns with the vessel that is next tothe nerve.

In any of the embodiments described herein, the focused ultrasoundenergy source is configured to track a movement of the nerve.

In any of the embodiments described herein, the focused ultrasoundenergy source is configured to track the movement of the nerve bytracking a movement of the blood vessel next to the nerve.

In any of the embodiments described herein, the focused ultrasoundenergy source is configured to aim towards the nerve by aiming towardsthe blood vessel that is surrounded by the nerve.

In any of the embodiments described herein, the system further includesa device for placement inside the patient, and a processor fordetermining a position using the device, wherein the focused ultrasoundenergy source is configured to deliver the ultrasound energy based atleast in part on the determined position.

In any of the embodiments described herein, the device is sized forinsertion into the blood vessel that is surrounded by the nerve.

In any of the embodiments described herein, the focused ultrasoundenergy source is configured to deliver the ultrasound energy towards theblood vessel at an angle anywhere between −10 degrees and −48 degreesrelative to a horizontal line connecting transverse processes of aspinal column, the angle directed from a lower torso to an upper torsoof the patient.

In accordance with some embodiments, a system for treatment of a nervesurrounding a blood vessel traveling to a kidney includes an ultrasoundenergy source for placement outside a patient wherein the ultrasoundenergy source comprises an array of ultrasound transducers, and aprogrammable interface, configured to control the ultrasound energysource to deliver focused ultrasound to a region surrounding a bloodvessel leading to the kidney through energizing one or more elements ofthe array in one or more phases, at an angle and offset to a centralaxis of the array to a tissue depth anywhere from 6 cm to 15 cm.

In any of the embodiments described herein, the focused ultrasoundenergy source comprises a transducer, and an angle of the focusedultrasound source is anywhere between 30 degrees to 80 degrees withrespect to a line traveling down a center of the transducer relative toa line connecting from the transducer to the blood vessel.

In any of the embodiments described herein, the focused ultrasoundenergy source is configured to provide the ultrasound energy to achievepartial ablation of the nerve.

In any of the embodiments described herein, the focused ultrasoundenergy source is configured to deliver the ultrasound energy to thenerve from multiple directions outside the patient while the focusedultrasound energy source is stationary relative to the patient.

In any of the embodiments described herein, the system further includesan imaging processor for determining a position of the blood vessel.

In any of the embodiments described herein, the imaging processorcomprises a CT device, a MRI device, a thermography device, an infraredimaging device, an optical coherence tomography device, a photoacousticimaging device, a PET imaging device, a SPECT imaging device, or anultrasound device.

In any of the embodiments described herein, the processor is configuredto operate the focused ultrasound energy source to target the nerve thatsurrounds the blood vessel during the ultrasound energy delivery basedon the determined position.

In any of the embodiments described herein, the processor is configuredto determine the position using a Doppler triangulation technique.

In any of the embodiments described herein, the focused ultrasoundenergy source is configured to deliver the ultrasound energy having anenergy level sufficient to decrease a sympathetic stimulus to thekidney, decrease an afferent signal from the kidney to an autonomicnervous system, or both.

In any of the embodiments described herein, the focused ultrasoundenergy source has an orientation so that the focused ultrasound energysource aims at a direction that aligns with the vessel that is next tothe nerve.

In any of the embodiments described herein, the focused ultrasoundenergy source is configured to track a movement of the nerve.

In any of the embodiments described herein, the focused ultrasoundenergy source is configured to track the movement of the nerve bytracking a movement of the blood vessel next to the nerve.

In any of the embodiments described herein, the focused ultrasoundenergy source is configured to aim towards the nerve by aiming towardsthe blood vessel that is surrounded by the nerve.

In any of the embodiments described herein, the system further includesa device for placement inside the patient, and a processor fordetermining a position using the device, wherein the focused ultrasoundenergy source is configured to deliver the ultrasound energy based atleast in part on the determined position.

In any of the embodiments described herein, the device is sized forinsertion into the blood vessel that is surrounded by the nerve.

In any of the embodiments described herein, the focused ultrasoundenergy source is configured to deliver the ultrasound energy towards theblood vessel at an angle anywhere between −10 degrees and −48 degreesrelative to a horizontal line connecting transverse processes of aspinal column, the angle directed from a lower torso to an upper torsoof the patient.

In accordance with some embodiments, a system for treatment of anautonomic nervous system of a patient includes a focused ultrasoundenergy source for placement outside the patient, wherein the focusedultrasound energy source is configured to deliver ultrasound energytowards a blood vessel with a surrounding nerve that is a part of theautonomic nervous system inside the patient, and wherein the focusedultrasound energy source is configured to deliver the ultrasound energybased on a position of an indwelling vascular catheter.

In any of the embodiments described herein, the focused ultrasoundenergy source comprises a transducer, and a angle of the focusedultrasound source is anywhere between 30 degrees to 80 degrees withrespect to a line traveling down a center of the transducer relative toa line connecting from the transducer to the blood vessel.

In any of the embodiments described herein, the focused ultrasoundenergy source is configured to provide the ultrasound energy to achievepartial ablation of the nerve.

In any of the embodiments described herein, the focused ultrasoundenergy source is configured to deliver the ultrasound energy to thenerve from multiple directions outside the patient while the focusedultrasound energy source is stationary relative to the patient.

In any of the embodiments described herein, the system further includesan imaging processor for determining a position of the blood vessel.

In any of the embodiments described herein, the imaging processorcomprises a CT device, a MRI device, a thermography device, an infraredimaging device, an optical coherence tomography device, a photoacousticimaging device, a PET imaging device, a SPECT imaging device, or anultrasound device.

In any of the embodiments described herein, the processor is configuredto operate the focused ultrasound energy source to target the nerve thatsurrounds the blood vessel during the ultrasound energy delivery basedon the determined position.

In any of the embodiments described herein, the processor is configuredto determine the position using a Doppler triangulation technique.

In any of the embodiments described herein, the focused ultrasoundenergy source is configured to deliver the ultrasound energy having anenergy level sufficient to decrease a sympathetic stimulus to thekidney, decrease an afferent signal from the kidney to an autonomicnervous system, or both.

In any of the embodiments described herein, the focused ultrasoundenergy source has an orientation so that the focused ultrasound energysource aims at a direction that aligns with the vessel that is next tothe nerve.

In any of the embodiments described herein, the focused ultrasoundenergy source is configured to track a movement of the nerve.

In any of the embodiments described herein, the focused ultrasoundenergy source is configured to track the movement of the nerve bytracking a movement of the blood vessel next to the nerve.

In any of the embodiments described herein, the focused ultrasoundenergy source is configured to aim towards the nerve by aiming towardsthe blood vessel that is surrounded by the nerve.

In any of the embodiments described herein, the focused ultrasoundenergy source is configured to deliver the ultrasound energy towards theblood vessel at an angle anywhere between −10 degrees and −48 degreesrelative to a horizontal line connecting transverse processes of aspinal column, the angle directed from a lower torso to an upper torsoof the patient.

In accordance with some embodiments, a system for treatment includes afocused ultrasound energy source for placement outside a patient,wherein the focused ultrasound energy source is configured to deliverultrasound energy towards a blood vessel with a surrounding nerve thatis a part of an autonomic nervous system inside the patient, and whereinthe focused ultrasound energy source is configured to deliver theultrasound energy towards the blood vessel at an angle anywhere between−10 degrees and −48 degrees relative to a horizontal line connectingtransverse processes of a spinal column, the angle directed from a lowertorso to an upper torso of the patient.

In any of the embodiments described herein, the focused ultrasoundenergy source comprises a transducer, and a angle of the focusedultrasound source is anywhere between 30 degrees to 80 degrees withrespect to a line traveling down a center of the transducer relative toa line connecting from the transducer to the blood vessel.

In any of the embodiments described herein, the focused ultrasoundenergy source is configured to provide the ultrasound energy to achievepartial ablation of the nerve.

In any of the embodiments described herein, the focused ultrasoundenergy source is configured to deliver the ultrasound energy to thenerve from multiple directions outside the patient while the focusedultrasound energy source is stationary relative to the patient.

In any of the embodiments described herein, the system further includesan imaging processor for determining a position of the blood vessel.

In any of the embodiments described herein, the imaging processorcomprises a CT device, a MRI device, a thermography device, an infraredimaging device, an optical coherence tomography device, a photoacousticimaging device, a PET imaging device, a SPECT imaging device, or anultrasound device.

In any of the embodiments described herein, the processor is configuredto operate the focused ultrasound energy source to target the nerve thatsurrounds the blood vessel during the ultrasound energy delivery basedon the determined position.

In any of the embodiments described herein, the processor is configuredto determine the position using a Doppler triangulation technique.

In any of the embodiments described herein, the focused ultrasoundenergy source is configured to deliver the ultrasound energy having anenergy level sufficient to decrease a sympathetic stimulus to thekidney, decrease an afferent signal from the kidney to an autonomicnervous system, or both.

In any of the embodiments described herein, the focused ultrasoundenergy source has an orientation so that the focused ultrasound energysource aims at a direction that aligns with the vessel that is next tothe nerve.

In any of the embodiments described herein, the focused ultrasoundenergy source is configured to track a movement of the nerve.

In any of the embodiments described herein, the focused ultrasoundenergy source is configured to track the movement of the nerve bytracking a movement of the blood vessel next to the nerve.

In any of the embodiments described herein, the focused ultrasoundenergy source is configured to aim towards the nerve by aiming towardsthe blood vessel that is surrounded by the nerve.

In any of the embodiments described herein, the system further includesa device for placement inside the patient, and a processor fordetermining a position using the device, wherein the focused ultrasoundenergy source is configured to deliver the ultrasound energy based atleast in part on the determined position.

In any of the embodiments described herein, the device is sized forinsertion into the blood vessel that is surrounded by the nerve.

In accordance with some embodiments, a method to apply a nerveinhibiting cloud surrounding a blood vessel includes creating atreatment plan, wherein the treatment plan prescribes application of thenerve inhibiting cloud towards at least a majority portion of acircumference of a blood vessel wall, and applying the nerve inhibitingcloud towards the majority portion of the circumference of the bloodvessel wall for a time sufficient to inhibit a function of a nerve thatsurrounds the blood vessel wall.

In any of the embodiments described herein, the nerve inhibiting cloudcomprises a cloud of light.

In any of the embodiments described herein, the nerve inhibiting cloudcomprises a gaseous cloud.

In any of the embodiments described herein, the nerve inhibiting cloudcomprises a heat cloud.

In any of the embodiments described herein, the nerve inhibiting cloudis applied using a transcutaneous energy source.

In any of the embodiments described herein, the nerve inhibiting cloudis applied using a transcutaneous energy source that is configured todeliver a focused ultrasound.

In any of the embodiments described herein, the nerve inhibiting cloudis applied using ionizing radiation.

In any of the embodiments described herein, the nerve inhibiting cloudis applied by delivering focused ultrasound, and the imaging devicecomprises an MRI device.

In any of the embodiments described herein, the method further includesobtaining an image of the blood vessel using an imaging device, whereinthe treatment plan is created using the image.

In accordance with some embodiments, a system to deliver a nerveinhibiting cloud to a region surrounding a blood vessel includes acatheter comprising a plurality of electrodes configured to apply acloud of heat, a processor storing a treatment plan that prescribes anapplication of the cloud of heat towards at least a majority of acircumference of a blood vessel wall surrounded by nerve, and anexternal detector configured for measuring temperature associated withthe application of the cloud of heat.

In any of the embodiments described herein, the external detectorcomprises an ultrasound device.

In any of the embodiments described herein, the external detectorcomprises an MRI device.

In any of the embodiments described herein, the catheter is configuredto be placed in a vein.

In any of the embodiments described herein, the catheter is configuredto be placed into a visceral artery.

In accordance with some embodiments, a system to deliver a nerveinhibiting treatment to a nerve region surrounding a blood vesselincludes a catheter comprising a component which is configured to beheated in response to an externally applied electromagnetic field, and adevice configured for applying the electromagnetic field through a skinof a patient to heat the component of the catheter, wherein the heatedcomponent provides a heat cloud to the nerve region surrounding theblood vessel.

In any of the embodiments described herein, the catheter comprises anexpandable member for pressing up against a wall of the blood vesselwhen the expandable member is expanded.

In any of the embodiments described herein, the device is furtherconfigured for measuring a temperature using the electromagnetic field.

In any of the embodiments described herein, the device comprises amagnetic resonance imaging device.

In any of the embodiments described herein, the device comprises anultrasound detection device.

In accordance with some embodiments, a method to deliver focusedultrasound energy from a position outside a skin of a patient to a nervesurrounding a blood vessel includes placing the patient on a table in asubstantially flat position, moving a transducer into a positioninferior to ribs, superior to an iliac crest, and lateral to a spine ofthe patient, maintaining the transducer at the position relative to thepatient, and delivering focused ultrasound energy through the skin ofthe patient without traversing bone, wherein the direction of thefocused ultrasound is directed from a lower torso to an upper torso ofthe patient.

In any of the embodiments described herein, the method further includesdetecting signals emanating from within the patient.

In any of the embodiments described herein, the method further includesdetecting signals emanating from an intravascular device inside thepatient.

In any of the embodiments described herein, the focused ultrasoundenergy is delivered to treat nerves inside the patient.

In any of the embodiments described herein, the nerves surrounds avessel, and the focused ultrasound energy is delivered to the nerves bytargeting the vessel.

In accordance with some embodiments, a system to deliver a nerveinhibiting treatment to a nerve region surrounding a blood vesselincludes a catheter comprising a component which is configured to beheated in response to an externally applied electromagnetic field, and amagnetic resonance device configured for applying the electromagneticfield through a skin of a patient to heat the component of the catheterto a level that is sufficient to treat the nerve region surrounding theblood vessel, and a temperature detection system configured to limit atemperature of the nerve region surrounding the blood vessel.

In any of the embodiments described herein, the magnetic resonancedevice includes the temperature detection system.

In any of the embodiments described herein, the temperature detectionsystem is inside the catheter.

In any of the embodiments described herein, the catheter is configuredto be steered based at least in part on a signal provided by themagnetic resonance system.

In any of the embodiments described herein, the magnetic resonancesystem is configured to move the catheter towards a wall of the bloodvessel.

In accordance with some embodiments, a system for treatment of a nervesurrounding a blood vessel traveling to a kidney includes an ultrasoundenergy source for placement outside a patient, wherein the ultrasoundenergy source comprises an array of ultrasound transducers, aprogrammable interface, configured to control the ultrasound energysource to deliver focused ultrasound to a region surrounding the bloodvessel leading to the kidney through energizing one or more elements ofthe array in one or more phases, and a magnetic resonance imaging systemcomprising a permanent magnet, wherein the magnetic resonance imagingsystem is operatively coupled to the programmable interface.

In any of the embodiments described herein, the system further includesan intravascular catheter device for placement into the vessel.

In any of the embodiments described herein, the system further includesa radiofrequency coil for placement around an abdomen of the patient.

In any of the embodiments described herein, the system further includesa positioning device for delivering focused ultrasound energy to theregion surrounding the blood vessel leading to the kidney.

In any of the embodiments described herein, the ultrasound energy sourceis configured to deliver the focused ultrasound at an angle and offsetto a central axis of the array to a tissue depth anywhere from 6 cm to15 cm.

In accordance with some embodiments, a system for treatment of a nervesurrounding a blood vessel traveling to a kidney includes an ultrasoundenergy source for placement outside a patient wherein the ultrasoundenergy source comprises an array of ultrasound transducers, aprogrammable interface, configured to control the ultrasound energysource to deliver focused ultrasound to a region surrounding the bloodvessel leading to the kidney through energizing one or more elements ofthe array in one or more phases, and a processor configured to determinea quality factor based at least on an amount of time the focusedultrasound is within a pre-determined distance from a target.

In any of the embodiments described herein, the pre-determined distanceis 500 microns.

In any of the embodiments described herein, the pre-determined distanceis 2 mm.

In any of the embodiments described herein, the processor is furtherconfigured to operate the ultrasound energy source based at least inpart on the quality factor.

In any of the embodiments described herein, the system further includesan intravascular catheter for placement into the vessel.

In any of the embodiments described herein, the intravascular catheteris configured to provide a signal related to movement of the regionbeing treated, and the processor is configured to operate the ultrasoundenergy source based at least in part on the signal.

In any of the embodiments described herein, the system further includesa motion tracking system coupled to the processor.

In any of the embodiments described herein, the ultrasound energy sourceis configured to deliver the focused ultrasound at an angle and offsetto a central axis of the array to a tissue depth anywhere from 6 cm to15 cm.

In accordance with some embodiments, a device to apply focusedultrasound to a patient includes a transducer configured to deliverfocused ultrasound to a blood vessel leading to a kidney, wherein thetransducer comprises a plurality of individually phaseable elements, anda membrane for coupling the ultrasound to the patient, a firstmechanical mover for positioning the transducer, wherein the firstmechanical mover is configured to operate with the phaseable elementssimultaneously to change a position of a focus of the transducer, and asecond mechanical mover for maintaining a pressure between the membraneof the transducer and a skin of the patient.

In any of the embodiments described herein, the membrane contains fluid,and pressure and temperature of the fluid is maintained at a constantlevel.

In any of the embodiments described herein, the device further includesan imaging system operatively coupled to the first mechanical mover.

In any of the embodiments described herein, the imaging system is an MRIsystem.

In any of the embodiments described herein, the imaging system is anultrasound system.

In any of the embodiments described herein, the imaging system isconfigured to detect an intravascular catheter.

In any of the embodiments described herein, the imaging system isconfigured to determine a three dimensional coordinate, and thetransducer is configured to deliver the ultrasound based at least inpart on the determined three dimensional coordinate.

Other and further aspects and features will be evident from reading thefollowing detailed description of the embodiments.

DESCRIPTION OF FIGURES

FIGS. 1A-1B depict the focusing of energy sources on nerves of theautonomic nervous system.

FIG. 1C depicts an imaging system to help direct the energy sources.

FIG. 1D depicts a system integration schematic.

FIG. 1E depicts a box diagram of an integrated system schematic.

FIG. 2 depicts targeting and/or therapeutic ultrasound delivered throughthe stomach to the autonomic nervous system posterior to the stomach.

FIG. 3A depicts focusing of energy waves on the renal nerves.

FIG. 3B depicts a coordinate reference frame for the treatment.

FIG. 3C depicts targeting catheters or energy delivery catheters placedin any of the renal vessels.

FIG. 3D depicts an image detection system of a blood vessel with atemporary fiducial placed inside the blood vessel, wherein the fiducialprovides positional information with respect to a reference frame.

FIG. 3E depicts a therapy paradigm for the treatment and assessment ofhypertension.

FIG. 4A depicts the application of energy to the autonomic nervoussystem surrounding the carotid arteries.

FIG. 4B depicts the application of energy to through the vessels of therenal hilum.

FIGS. 5A-5B depict the application of focused energy to the autonomicnervous system of the eye.

FIG. 5C depicts the application of energy to other autonomic nervoussystem structures.

FIG. 6 depicts the application of constricting lesions to the kidneydeep inside the calyces of the kidney.

FIG. 7A depicts a patient in an imaging system receiving treatment withfocused energy waves.

FIG. 7B depicts visualization of a kidney being treated.

FIG. 7C depicts a close up view of the renal nerve region of the kidneybeing treated.

FIG. 7D depicts an algorithmic method to treat the autonomic nervoussystem using MRI and energy transducers.

FIG. 7E depicts a geometric model obtained from cross-sectional imagesof the area of the aorta and kidneys along with angles of approach tothe blood vessels and the kidney.

FIG. 7F depicts a close up image of the region of treatment.

FIG. 7G depicts the results of measurements from a series of crosssectional image reconstructions.

FIG. 7H depicts the results of measurements from a series ofcross-sectional images from a patient in a more optimized position.

FIG. 7I depicts an algorithmic methodology to apply treatment to thehilum of the kidney and apply energy to the renal blood vessels.

FIG. 7J depicts a clinical algorithm to apply energy to the blood vesselleading to the kidney.

FIG. 7K depicts a device to diagnose proper directionality to applyenergy to the region of the kidney.

FIG. 7L depicts a methodology to ablate a nerve around an artery byapplying a cloud of heat or neurolytic substance.

FIG. 7M depicts a clinical algorithm to apply energy along a renal bloodvessel.

FIG. 7N depicts a cloud of heat to affect the nerves leading to thekidney.

FIG. 7O depicts a close up of a heat cloud as well as nerves leading tothe kidney.

FIG. 8A depicts a percutaneous approach to treating the autonomicnervous system surrounding the kidneys.

FIG. 8B depicts an intravascular approach to treating or targeting theautonomic nervous system.

FIG. 8C depicts a percutaneous approach to the renal hila using a CTscan and a probe to reach the renal blood vessels.

FIG. 8D depicts an intravascular detection technique to characterize theinterpath between the blood vessel and the skin.

FIGS. 8E-8F depict cross sectional images with focused energy travelingfrom a posterior direction.

FIGS. 9A-9C depicts the application of energy from inside the aorta toregions outside the aorta to treat the autonomic nervous system.

FIG. 10 depicts steps to treat a disease using HIFU while monitoringprogress of the treatment as well as motion.

FIG. 11A depicts treatment of brain pathology using cross sectionalimaging.

FIG. 11B depicts an image on a viewer showing therapy of the region ofthe brain being treated.

FIG. 11C depicts another view of a brain lesion as might be seen on animaging device which assists in the treatment of the lesion.

FIG. 12 depicts treatment of the renal nerve region using a laparoscopicapproach.

FIG. 13 depicts a methodology for destroying a region of tissue usingimaging markers to monitor treatment progress.

FIG. 14 depicts the partial treatment of portions of a nerve bundleusing converging imaging and therapy wave.

FIGS. 15A-15C depict the application of focused energy to the vertebralcolumn to treat various spinal pathologies including therapy of thespinal or intravertebral nerves.

FIG. 16A depicts the types of lesions which are created around the renalarteries to affect a response.

FIG. 16B depicts a simulation of ultrasound around a blood vessel Isupport of FIG. 16A.

FIG. 16C depicts data from ultrasound energy applied to the renal bloodvessels and the resultant change in norepinephrine levels.

FIGS. 16D-16H depict a simulation of multiple treatment spots along ablood vessel.

FIGS. 161-16K depict various treatment plans of focused energy around ablood vessel.

FIGS. 16L-16M depict data indicating that focused energy applied fromthe outside can affect sympathetic nerve supply to organs.

FIG. 17A depicts the application of multiple transducers to treatregions of the autonomic nervous system at the renal hilum.

FIGS. 17B-17C depict methods for using imaging to direct treatment of aspecific region surrounding an artery as well as display the predictedlesion morphology.

FIG. 17D depicts a method for localizing HIFU transducers relative toDoppler ultrasound signals.

FIG. 17E depicts an arrangement of transducers relative to a target.

FIG. 17F depicts ablation zones in a multi-focal region incross-section.

FIG. 18 depicts the application of energy internally within the kidneyto affect specific functional changes at the regional level within thekidney.

FIG. 19A depicts the direction of energy wave propagation to treatregions of the autonomic nervous system around the region of the kidneyhilum.

FIG. 19B depicts a schematic of a B mode ultrasound from a directiondetermined through experimentation to provide access to the renal hilumwith HIFU.

FIGS. 19C-19D depict a setup for the treatment of the renal bloodvessels along with actual treatment of the renal blood vessels.

FIG. 19E is a schematic algorithm of the treatment plan for treatmentshown in FIG. 19C-D.

FIG. 20 depicts the application of ultrasound waves through the wall ofthe aorta to apply a therapy to the autonomic nervous system.

FIG. 21A depicts application of focused energy to the ciliary musclesand processes of the anterior region of the eye.

FIG. 21B depicts the application of focused non-ablative energy to theback of the eye to enhance drug or gene delivery or another therapy suchas ionizing radiation.

FIG. 22 depicts the application of focused energy to nerves surroundingthe knee joint to affect nerve function in the joint.

FIGS. 23A-23B depict the application of energy to the fallopian tube tosterilize a patient.

FIG. 24 depicts an algorithm to assess the effect of the neuralmodulation procedure on the autonomic nervous system. After a procedureis performed on the renal nerves, assessment of the autonomic responseis performed by, for example, simulating the autonomic nervous system inone or more places.

FIG. 25 depicts an optimized position of a device to apply therapy tointernal nerves.

FIG. 26A depicts positioning of a patient to obtain parameters forsystem design.

FIG. 26B depicts a device design based on the information learned fromfeasibility studies.

FIG. 27 depicts a clinical paradigm for treating the renal nerves of theautonomic nervous system based on feasibility studies.

FIGS. 28A-28C depict a treatment positioning system for a patientincorporating a focused ultrasound system.

FIGS. 28D-28I illustrate system configurations for a system to treatnerves inside a patient using focused energy.

FIG. 28J is a depiction of an underlining for the patient with partialor fully inflated elements.

FIG. 28K is a configuration of a system built into a table for apatient.

FIGS. 29A-D depict results of studies applying focused energy to nervessurrounding arteries and of ultrasound studies to visualize the bloodvessels around which the nerves travel.

FIG. 29E depicts the results of design processes in which the angle,length, and surface area from CT scans is quantified.

FIGS. 30A-30I depict results of simulations to apply focused ultrasoundto the region of a renal artery with a prototype device design based onsimulations.

FIG. 30J depicts an annular array customized to treat the anatomy shownfor the kidney and renal blood vessels above.

FIG. 30K highlights the annular array and depicts the imaging componentat the apex.

FIGS. 30L-N depict various cutouts for ultrasound imaging probes.

FIGS. 30O-P depict projection from the proposed transducer designs.

FIG. 30Q is a depiction of a focal zone created by the therapeutictransducer(s) to focus a single region.

FIGS. 30R-30S depict a multi-element array in a pizza slice shape yetwith many square elements.

FIGS. 30T-30U depict simulations of the annular array specific for theanatomy to be treated around a kidney of a patient.

FIG. 30V depicts a housing for the custom array.

FIG. 30W depicts focusing of energy from the custom array along a bloodvessel.

FIG. 31A depicts an off center focus from an alternative arrangement ofthe annular array transducer.

FIG. 31B depicts focusing of energy from an alternative embodiment ofthe customized transducer array in the clinical embodiment in which acatheter is placed within the patient.

FIG. 31C is a depiction of a movement mechanism within a patient table.

FIG. 31D is an overall block diagram of the system subsystems.

DETAILED DESCRIPTION

Hypertension is a disease of extreme national and internationalimportance. There are 80 million patients in the US alone who havehypertension and over 200 million in developed countries worldwide. Inthe United States, there are 60 million patients who have uncontrolledhypertension, meaning that they are either non-compliant or cannot takethe medications because of the side effect profile. Up to 10 millionpeople might have completely resistant hypertension in which they do notreach target levels no matter what the medication regimen. Themorbidities associated with uncontrolled hypertension are profound,including stroke, heart attack, kidney failure, peripheral arterialdisease, etc. A convenient and straightforward minimally invasiveprocedure to treat hypertension would be a very welcome advance in thetreatment of this disease.

Congestive Heart Failure (“CHF”) is a condition which occurs when theheart becomes damaged and blood flow is reduced to the organs of thebody. If blood flow decreases sufficiently, kidney function becomesaltered, which results in fluid retention, abnormal hormone secretionsand increased constriction of blood vessels. These results increase theworkload of the heart and further decrease the capacity of the heart topump blood through the kidneys and circulatory system.

It is believed that progressively decreasing perfusion of the kidneys isa principal non-cardiac cause perpetuating the downward spiral of CHF.For example, as the heart struggles to pump blood, the cardiac output ismaintained or decreased and the kidneys conserve fluid and electrolytesto maintain the stroke volume of the heart. The resulting increase inpressure further overloads the cardiac muscle such that the cardiacmuscle has to work harder to pump against a higher pressure. The alreadydamaged cardiac muscle is then further stressed and damaged by theincreased pressure. Moreover, the fluid overload and associated clinicalsymptoms resulting from these physiologic changes result in additionalhospital admissions, poor quality of life, and additional costs to thehealth care system. In addition to exacerbating heart failure, kidneyfailure can lead to a downward spiral and further worsening kidneyfunction. For example, in the forward flow heart failure describedabove, (systolic heart failure) the kidney becomes ischemic. In backwardheart failure (diastolic heart failure), the kidneys become congestedvis-à-vis renal vein hypertension. Therefore, the kidney can contributeto its own worsening failure.

The functions of the kidneys can be summarized under three broadcategories: filtering blood and excreting waste products generated bythe body's metabolism; regulating salt, water, electrolyte and acid-basebalance; and secreting hormones to maintain vital organ blood flow.Without properly functioning kidneys, a patient will suffer waterretention, reduced urine flow and an accumulation of waste toxins in theblood and body. These conditions result from reduced renal function orrenal failure (kidney failure) and are believed to increase the workloadof the heart. In a CHF patient, renal failure will cause the heart tofurther deteriorate as fluids are retained and blood toxins accumulatedue to the poorly functioning kidneys. The resulting hypertension alsohas dramatic influence on the progression of cerebrovascular disease andstroke.

The autonomic nervous system is a network of nerves which affect almostevery organ and physiologic system to a variable degree. Generally, thesystem is composed of sympathetic and parasympathetic nerves. Forexample, the sympathetic nerves to the kidney traverse the sympatheticchain along the spine and synapse within the ganglia of the chain orwithin the celiac ganglia, then proceeding to innervate the kidney viapost-ganglionic fibers inside the “renal nerves.” Within the renalnerves, which travel along the renal hila (artery and to some extent thevein), are the post-ganglionic sympathetic nerves and the afferentnerves from the kidney. The afferent nerves from the kidney travelwithin the dorsal root (if they are pain fibers) and into the anteriorroot if they are sensory fibers, then into the spinal cord andultimately to specialized regions of the brain. The afferent nerves,baroreceptors and chemoreceptors, deliver information from the kidneysback to the sympathetic nervous system via the brain; their ablation orinhibition is at least partially responsible for the improvement seen inblood pressure after renal nerve ablation, or dennervation, or partialdisruption. It has also been suggested and partially provenexperimentally that the baroreceptor response at the level of thecarotid sinus is mediated by the renal artery afferent nerves such thatloss of the renal artery afferent nerve response blunts the response ofthe carotid baroreceptors to changes in arterial blood pressure(American J. Physioogy and Renal Physiology 279:F491-F501, 2000).

It has been established in animal models that the heart failurecondition results in abnormally high sympathetic activation of thekidneys. An increase in renal sympathetic nerve activity leads todecreased removal of water and sodium from the body, as well asincreased renin secretion which stimulates aldosterone secretion fromthe adrenal gland. Increased renin secretion can lead to an increase inangiotensin II levels which leads to vasoconstriction of blood vesselssupplying the kidneys as well as systemic vasoconstriction, all of whichlead to a decrease in renal blood flow and hypertension. Reduction insympathetic renal nerve activity, e.g., via de-innervation, may reversethese processes and in fact has been shown to in the clinic. Similarly,in obese patients, the sympathetic drive is intrinsically very high andis felt to be one of the causes of hypertension in obese patients.

Recent clinical work has shown that de-innervation of the renalsympathetic chain and other nerves which enter the kidney through thehilum can lead to profound systemic effects in patients (rats, dogs,pig, sheep, humans) with hypertension, heart failure, and other organsystem diseases. Such treatment can lead to long term reduction in theneed for blood pressure medications and improvements in blood pressure(O'Brien Lancet 2009 373; 9681). The devices used in this trial werehighly localized radiofrequency (RF) ablation to ablate the renal arteryadventitia with the presumption that the nerves surrounding the renalartery are being inhibited in the heating zone as well. The procedure isperformed in essentially a blind fashion in that the exact location ofthe nerve plexus is not known prior to, during, or after the procedure.In addition, the wall of the renal artery is invariably damaged by theRF probe and patients whose vessels have a great deal of atherosclerosiscannot be treated safely. In addition, depending on the distance of thenerves from the vessel wall, the energy may not consistently lead toablation or interruption. Finally, the use of internal catheters may notallow for treatment inside the kidney or inside the aorta if moreselective. In many cases, it is required to create a spiral along thelength and inside the blood vessel to avoid circumferential damage tothe vessel.

Cross-sectional imaging can be utilized to visualize the internalanatomy of patients via radiation (CT) or magnetic fields (MRI).Ultrasound can also be utilized to obtain cross-sections of specificregions but only at high frequencies; therefore, ultrasound is typicallylimited to imaging superficial body regions. CT and MRI are often moreamenable to cross sectional imaging because the radiation penetrateswell into tissues. In addition, the scale of the body regions ismaintained such that the anatomy within the coordinate referencesremains intact relative to one another; that is, distances betweenstructures can be measured.

With ultrasound, scaling can be more difficult because of unequalpenetration as the waves propagate deeper through the tissue. CT scansand MRIs and even ultrasound devices can be utilized to create threedimensional representations and reconstructed cross-sectional images ofpatients; anatomy can be placed in a coordinate reference frame using athree dimensional representation. Once in the reference frame, energydevices (transducers) can be placed in position and energy emittingdevices directed such that specific regions of the body are targeted.Once knowledge of the transducer position is known relative to theposition of the target in the patient body, energy can be delivered tothe target.

Ultrasound is a cyclically generated sound pressure wave with afrequency greater than the upper limit of human hearing . . . 20kilohertz (kHz). In medicine, ultrasound is widely utilized because ofits ability to penetrate tissues. Reflection of the sound waves revealsa signature of the underlying tissues and as such, ultrasound can beused extensively for diagnostics and potentially therapeutics as well inthe medical field. As a therapy, ultrasound has the ability to bothpenetrate tissues and can be focused to create ablation zones. Becauseof its simultaneous ability to image, ultrasound can be utilized forprecise targeting of lesions inside the body. Ultrasound intensity ismeasured by the power per cm² (for example, W/cm² at the therapeutictarget region). Generally, high intensity refers to intensities over0.1-5 kW/cm². Low intensity ultrasound encompasses the range up to0.01-0.10 kW/cm² from about 1 or 10 Watts per cm².

Ultrasound can be utilized for its forward propagating waves andresulting reflected waves or where energy deposition in the tissue andeither heating or slight disruption of the tissues is desired. Forexample, rather than relying on reflections for imaging, lower frequencyultrasonic beams (e.g. <1 MHz) can be focused at a depth within tissue,creating a heating zone or a defined region of cavitation in whichmicro-bubbles are created, cell membranes are opened to admit bioactivemolecules, or damage is otherwise created in the tissue. These featuresof ultrasound generally utilize frequencies in the 0.25 Megahertz (MHz)to 10 MHz range depending on the depth required for effect. Focusing is,or may be, required so that the surface of the tissue is not excessivelyinjured or heated by single beams. In other words, many single beams canbe propagated through the tissue at different angles to decrease theenergy deposition along any single path yet allow the beams to convergeat a focal spot deep within the tissue. In addition, reflected beamsfrom multiple angles may be utilized in order to create a threedimensional representation of the region to be treated in a coordinatespace.

It is important when planning an ultrasound therapy that sharp,discontinuous interfaces be avoided. For example, bowel, lung, bonewhich contain air and/or bone interfaces constitute sharp boundarieswith soft tissues. These interfaces make the planning and therapy moredifficult. If however, the interfaces can be avoided, then treatment canbe greatly simplified versus what has to be done for the brain (e.g.MR-guided HIFU) where complex modeling is required to overcome the veryhigh attenuation of the cranium. Data provided below reveals a discoverythrough extensive experimentation as to how to achieve this treatmentsimplicity for treatment of specific structures such as nervessurrounding blood vessels.

Time of flight measurements with ultrasound can be used to range find,or find distances between objects in tissues. Such measurements can beutilized to place objects such as vessels into three dimensionalcoordinate reference frames so that energy can be utilized to target thetissues. SONAR is the acronym for sound navigation and ranging and is amethod of acoustic localization. Sound waves are transmitted through amedium and the time for the sound to reflect back to the transmitter isindicative of the position of the object of interest. Doppler signalsare generated by a moving object. The change in the forward andreflected wave results in a velocity for the object.

The concept of speckle tracking is one in which the reflections ofspecific tissues is defined and tracked over time (IEEE Transactions onUltrasonics, Ferroelectrics, AND Frequency Control, Vol. 57, no. 4,April 2010). With defined points in space, a three dimensionalcoordinate reference can be created through which energy can be appliedto specific and well-defined regions. To track a speckle, an ultrasoundimage is obtained from a tissue. Light and dark spots are defined in theimage, these light and dark spots representing inhomgeneities in thetissues. The inhomegeneities are relatively constant, being essentiallyproperties of the tissue. With relatively constant markers in thetissue, tracking can be accomplished using real time imaging of themarkers. With more than one plane of ultrasound, the markers can berelated in three dimensions relative to the ultrasound transducer and atherapeutic energy delivered to a defined position within the threedimensional field.

At the time one or more of these imaging modalities is utilized todetermine the position of the target in three dimensions, then a therapycan be both planned and applied to a specific region within the threedimensional volume.

Lithotripsy was introduced in the early part of the 1980's. Lithotripsyutilizes shockwaves to treat stones in the kidney. The Dornierlithotripsy system was the first system produced for this purpose. Thelithotripsy system sends ultrasonic waves through the patient's body tothe kidney to selectively heat and vibrate the kidney stones; that is,selectively over the adjacent tissue. At the present time, lithotripsysystems do not utilize direct targeting and imaging of the kidney stoneregion. A tremendous advance in the technology would be to image thestone region and target the specific region in which the stone residesso as to minimize damage to surrounding structures such as the kidney.In the case of a kidney stone, the kidney is in fact the speckle,allowing for three dimensional targeting and tracking off its image withsubsequent application of ultrasound waves to break up the stone. In theembodiments which follow below, many of the techniques and imagingresults described can be applied to clinical lithotripsy. For example,imaging of the stone region and tracking of the stone region can lead toan improved targeting system for breaking up kidney stones. Rather thanwasting energy on regions which don't contain stones and destroyinghealthy kidney, energy can be concentrated on the portions of the kidneywhich contain the stones.

Histotripsy is a term given to a technique in which tissue isessentially vaporized using cavitation rather than heating(transcutaneous non-thermal mechanical tissue fractionation). These miniexplosions do not require high temperature and can occur in less than asecond. The generated pressure wave is in the range of megapascals (MPa)and even up to or exceeding 100 MPa. To treat small regions of tissuevery quickly, this technique can be very effective. The border of theviable and non-viable tissue is typically very sharp and the mechanismof action has been shown to be cellular disruption.

In one embodiment, ultrasound is focused on the region of the renalarteries and/or veins from outside the patient; the ultrasound isdelivered from multiple angles to the target, thereby overcoming many ofthe deficiencies in previous methods and devices put forward to ablaterenal sympathetic nerves which surround the renal arteries.

Specifically, one embodiment allows for precise visualization of theablation zone so that the operator can be confident that the correctregion is ablated and that the incorrect region is not ablated. Becausesome embodiments do not require a puncture in the skin, they areconsiderably less invasive, which is more palatable and safer from thepatient standpoint. Moreover, unusual anatomies and atheroscleroticvessels can be treated using external energy triangulated on the renalarteries to affect the sympathetic and afferent nerves to and from thekidney respectively.

With reference to FIG. 1A, the human renal anatomy includes the kidneys100 which are supplied with oxygenated blood by the renal arteries 200and are connected to the heart via the abdominal aorta 300. Deoxygenatedblood flows from the kidneys to the heart via the renal veins (notshown) and thence the inferior vena cava (not shown). The renal anatomyincludes the cortex, the medulla, and the hilum. Blood is delivered tothe cortex where it filters through the glomeruli and is then deliveredto the medulla where it is further filtered through a series ofreabsorption and filtration steps in the loops of henle and individualnephrons; the ultrafiltrate then percolates to the ureteral collectingsystem and is delivered to the ureters and bladder for ultimateexcretion.

The hila is the region where the major vessels (renal artery and renalvein) and nerves 150 (efferent sympathetic, afferent sensory, andparasympathetic nerves) travel to and from the kidneys. The renal nerves150 contain post-ganglionic efferent nerves which supply sympatheticinnervation to the kidneys. Afferent sensory nerves travel from thekidney to the central nervous system and are postganglionic afferentnerves with nerve bodies in the central nervous system. These nervesdeliver sensory information to the central nervous system and arethought to regulate much of the sympathetic outflow from the centralnervous system to all organs including the skin, heart, kidneys, brain,etc.

In one method, energy is delivered from outside a patient, through theskin, and to the renal afferent and/or renal efferent nerves. Microwave,light, vibratory (e.g. acoustic), ionizing radiation might be utilizedin some or many of the embodiments.

Energy transducers 500 (FIG. 1A) deliver energy transcutaneously to theregion of the sympathetic ganglia 520 or the post-ganglionic renalnerves 150 or the nerves leading to the adrenal gland 400. The energy isgenerated from outside the patient, from multiple directions, andthrough the skin to the region of the renal nerves 624 which surroundthe renal artery 620 or the sympathetic ganglion 622 which house thenerves. The energy can be focused or non-focused but in one preferredembodiment, the energy is focused with high intensity focused ultrasound(HIFU) or low intensity focused ultrasound.

Focusing with low intensity focused ultrasound (LIFU) may also occurintentionally as a component of the HIFU (penumbra regions) orunintentionally. The mechanism of nerve inhibition is variable dependingon the “low” or “high” of focused ultrasound. Low energy might includeenergy levels of 25 W/cm²-200 W/cm². Higher intensity includes energylevels from 200 W/cm² to 1 MW/cm². Focusing occurs by delivering energyfrom at least two different angles through the skin to meet at a focalpoint where the highest energy intensity and density occurs. At thisspot, a therapy is delivered and the therapy can be sub-threshold nerveinterruption (partial ablation), ablation (complete interruption) of thenerves, controlled interruption of the nerve conduction apparatus,partial ablation, or targeted drug delivery. The region can be heated toa temperature of less than 60 degrees Celsius for non-ablative therapyor can be heated greater than 60 degrees Celsius for heat baseddestruction (ablation). To ablate the nerves, even temperatures in the40 degree Celsius range can be used and if generated for a time periodgreater than several minutes, will result in ablation. For temperaturesat about 50 degrees Celsius, the time might be under one minute. Heatingaside, a vibratory effect for a much shorter period of time attemperatures below 60 degrees Celsius can result in partial or completeparalysis or destruction of the nerves. If the temperature is increasedbeyond 50-60 degrees Celsius, the time required for heating is decreasedconsiderably to affect the nerve via the sole mechanism of heating. Insome embodiments, an imaging modality is included as well in the system.The imaging modality can be ultrasound based, MRI based, or CT (X-Ray)based. The imaging modality can be utilized to target the region ofablation and determined the distances to the target.

The delivered energy can be ionizing or non-ionizing energy in someembodiments. Forms of non-ionizing energy can include electromagneticenergy such as a magnetic field, light, an electric field,radiofrequency energy, and light based energy. Forms of ionizing energyinclude x-ray, proton beam, gamma rays, electron beams, and alpha rays.In some embodiments, the energy modalities are combined. For example,heat ablation of the nerves is performed and then ionizing radiation isdelivered to the region to prevent re-growth of the nerves.

Alternatively, ionizing radiation is applied first as an ablationmodality and then heat applied afterward in the case of re-growth of thetissue as re-radiation may not be possible (complement or multimodalityenergy utilization). Ionizing radiation may prevent or inhibit there-growth of the nervous tissue around the vessel if there is indeedre-growth of the nervous tissue. Therefore, another method of treatingthe nerves is to first heat the nerves and then apply ionizing radiationto prevent re-growth.

Other techniques such as photodynamic therapy including aphotosensitizer and light source to activate the photosensitizer can beutilized as a manner to combine modalities. Most of thesephotosensitizing agents are also sensitive to ultrasound energy yieldingthe same photoreactive species as if it were activated by light. Aphotoreactive or photosensitive agent can be introduced into the targetarea prior to the apparatus being introduced into the blood vessel; forexample, through an intravenous injection, a subcutaneous injection,etc. However, it will be understood that if desired, the apparatus canoptionally include a lumen for delivering a photoreactive agent into thetarget area. The resulting embodiments are likely to be particularlybeneficial where uptake of the photoreactive agent into the targettissues is relatively rapid, so that the apparatus does not need toremain in the blood vessel for an extended period of time while thephotoreactive agent is distributed into and absorbed by the targettissue.

Light source arrays can include light sources that provide more than onewavelength or waveband of light. Linear light source arrays areparticularly useful to treat elongate portions of tissue. Light sourcearrays can also include reflective elements to enhance the transmissionof light in a preferred direction. For example, devices can beneficiallyinclude expandable members such as inflatable balloons to occlude bloodflow (which can interfere with the transmission of light from the lightsource to the intended target tissue) and to enable the apparatus to becentered in a blood vessel. Another preferred embodiment contemplates atranscutaneous PDT method where the photosensitizing agent deliverysystem comprises a liposome delivery system consisting essentially ofthe photosensitizing agent. Light sources may be directed at a focusfrom within a blood vessel to a position outside a blood vessel.Infrared, Red, Blue, Green, and ultraviolet light may be used fromwithin a blood vessel to affect nervous tissue outside the blood vessel.Light emitting diodes may be introduced via catheter to the vein, theartery, the aorta, etc. After introduction of the photoreactive agent(e.g. via intravenous, subcutaneous, transarterial, transvenousinjection), the light is applied through the blood vessel wall in acloud of energy which activates the photoreactive agents.

Yet another embodiment is drawn to a method for transcutaneousultrasonic therapy of a target lesion in a mammalian subject utilizing asensitizer agent. In this embodiment, the biochemical compound isactivated by ultrasound through the following method:

1) administering to the subject a therapeutically effective amount of anultrasonic sensitizing agent or a ultrasonic sensitizing agent deliverysystem or a prodrug, where the ultrasonic sensitizing agent orultrasonic sensitizing agent delivery system or prodrug selectivelybinds to the thick or thin neointimas, nerve cells, nerve sheaths, nervenuclei, arterial plaques, vascular smooth muscle cells and/or theabnormal extracellular matrix of the site to be treated. Nervecomponents can also be targeted, for example, the nerve sheath, myelin,S-100 protein. This step is followed by irradiating at least a portionof the subject with ultrasonic energy at a frequency that activates theultrasonic sensitizing agent or if a prodrug, by a prodrug productthereof, where the ultrasonic energy is provided by an ultrasonic energyemitting source. This embodiment further provides, optionally, that theultrasonic therapy drug is cleared from non-target tissues of thesubject prior to irradiation.

A preferred embodiment contemplates a method for transcutaneousultrasonic therapy of a target tissue, where the target tissue is closeto a blood vessel. Other preferred embodiments contemplate that theultrasonic energy emitting source is external to the patient's intactskin layer or is inserted underneath the patient's intact skin layer,but is external to the blood vessel to be treated. An additionalpreferred embodiment provides that the ultrasonic sensitizing agent isconjugated to a ligand and more preferably, where the ligand is selectedfrom the group consisting of: a target lesion specific antibody; atarget lesion specific peptide and a target lesion specific polymer.Other preferred embodiments contemplate that the ultrasonic sensitizingagent is selected from the group consisting of: indocyanine green (ICG);methylene blue; toluidine blue; aminolevulinic acid (ALA); chlorincompounds; phthalocyanines; porphyrins; purpurins; texaphyrins; and anyother agent that absorbs light in a range of 500 nm-1100 nm. A preferredembodiment contemplates that the photosensitizing agent is indocyaninegreen (ICG).

Other embodiments are drawn to the presently disclosed methods oftranscutaneous PDT, where the light source is positioned in proximity tothe target tissue of the subject and is selected from the groupconsisting of: an LED light source; an electroluminesent light source;an incandescent light source; a cold cathode fluorescent light source;organic polymer light source; and inorganic light source. A preferredembodiment includes the use of an LED light source.

Yet other embodiments of the presently disclosed methods are drawn touse of light of a wavelength that is from about 500 nm to about 1100 nm,preferably greater than about 650 nm and more preferably greater thanabout 700 nm. A preferable embodiment of the present method is drawn tothe use of light that results in a single photon absorption mode by thephotosensitizing agent.

Additional embodiments include compositions of photosensitizer targeteddelivery system comprising: a photosensitizing agent and a ligand thatbinds a receptor on the target tissue with specificity. Preferably, thephotosensitizing agent of the targeted delivery system is conjugated tothe ligand that binds a receptor on the target (nerve or adventitialwall of blood vessel) with specificity. More preferably, the ligandcomprises an antibody that binds to a receptor. Most preferably, thereceptor is an antigen on thick or thin neointimas, intimas, adventitiaof arteries, arterial plaques, vascular smooth muscle cells and/or theextracellular matrix of the site to be treated.

A further preferred embodiment contemplates that the photosensitizingagent is selected from the group consisting of: indocyanine green (ICG);methylene blue; toluidine blue; aminolevulinic acid (ALA); chlorincompounds; phthalocyanines; porphyrins; purpurins; texaphyrins; and anyother agent that absorbs light in a range of 500 nm-1100 nm.

Other photosensitizers that may be used with embodiments describedherein are known in the art, including, photofrin. RTM, syntheticdiporphyrins and dichlorins, phthalocyanines with or without metalsubstituents, chloroaluminum phthalocyanine with or without varyingsubstituents, chloroaluminum sulfonated phthalocyanine, O-substitutedtetraphenyl porphyrins, 3,1-meso tetrakis (o-propionamido phenyl)porphyrin, verdins, purpurins, tin and zinc derivatives ofoctaethylpurpurin, etiopurpurin, hydroporphyrins, bacteriochlorins ofthe tetra(hydroxyphenyl) porphyrin series, chlorins, chlorin e6,mono-1-aspartyl derivative of chlorin e6, di-l-aspartyl derivative ofchlorin e6, tin(IV) chlorin e6, meta-tetrahydroxphenylchlorin,benzoporphyrin derivatives, benzoporphyrin monoacid derivatives,tetracyanoethylene adducts of benzoporphyrin, dimethylacetylenedicarboxylate adducts of benzoporphyrin, Diels-Adler adducts,monoacid ring “a” derivative of benzoporphyrin, sulfonated aluminum PC,sulfonated AlPc, disulfonated, tetrasulfonated derivative, sulfonatedaluminum naphthalocyanines, naphthalocyanines with or without metalsubstituents and with or without varying substituents, zincnaphthalocyanine, anthracenediones, anthrapyrazoles, aminoanthraquinone,phenoxazine dyes, phenothiazine derivatives, chalcogenapyrylium dyes,cationic selena and tellurapyrylium derivatives, ring-substitutedcationic PC, pheophorbide derivative, pheophorbide alpha and ether orester derivatives, pyropheophorbides and ether or ester derivatives,naturally occurring porphyrins, hematoporphyrin, hematoporphyrinderivatives, hematoporphyrin esters or ethers, protoporphyrin,ALA-induced protoporphyrin IX, endogenous metabolic precursors,5-aminolevulinic acid benzonaphthoporphyrazines, cationic imminiumsalts, tetracyclines, lutetium texaphyrin, tin-etio-purpurin,porphycenes, benzophenothiazinium, pentaphyrins, texaphyrins andhexaphyrins, 5-amino levulinic acid, hypericin, pseudohypericin,hypocrellin, terthiophenes, azaporphyrins, azachlorins, rose bengal,phloxine B, erythrosine, iodinated or brominated derivatives offluorescein, merocyanines, nile blue derivatives, pheophytin andchlorophyll derivatives, bacteriochlorin and bacteriochlorophyllderivatives, porphocyanines, benzochlorins and oxobenzochlorins,sapphyrins, oxasapphyrins, cercosporins and related fungal metabolitesand combinations thereof.

Several photosensitizers known in the art are FDA approved andcommercially available. In a preferred embodiment, the photosensitizeris a benzoporphyrin derivative (“BPD”), such as BPD-MA, alsocommercially known as BPD Verteporfin or “BPD” (available from QLT).U.S. Pat. No. 4,883,790 describes BPD compositions. BPD is asecond-generation compound, which lacks the prolonged cutaneousphototoxicity of Photofrin® (Levy (1994) Semin Oncol 21: 4-10). BPD hasbeen thoroughly characterized (Richter et al., (1987) JNCI79:1327-1331), (Aveline et al. (1994) Photochem Photobiol 59:328-35),and it has been found to be a highly potent photosensitizer for PDT.

In a preferred embodiment, the photosensitizer is tin ethyletiopurpurin, commercially known as purlytin (available from Miravant).

In some embodiments, external neuromodulation is performed in which lowenergy ultrasound is applied to the nerve region to modulate the nerves.For example, it has been shown in the past that low intensity (e.g.non-thermal) ultrasound can affect nerves at powers which range from30-500 W/Cm² whereas HIFU (thermal modulation), which by definitiongenerates heat at a focus point, requires power levels exceeding 1000W/Cm². The actual power flux to the region to be ablated is dependent onthe environment including surrounding blood flow and other structures.With low intensity ultrasound, the energy does not have to be sostrictly focused to the target because it's a non-ablative energy; thatis, the vibration or mechanical pressure may be the effector energy andthe target may have a different threshold for effect depending on thetissue. However, even low energy ultrasound may require focusing ifexcessive heat to the skin is a worry or if there are other susceptiblestructures in the path and only a pinpoint region of therapy is desired.Nonetheless, transducers 500 in FIG. 1 a provide the ability to apply arange of different energy and power levels as well as modelingcapability to target different regions and predict the response.

In FIG. 1 a, and in one embodiment, a renal artery 640 is detected withthe assistance of imaging devices 600 such as Doppler ultrasound,infrared imaging, thermal imaging, B-mode ultrasound, MRI, or a CT scan.With an image of the region to be treated, measurements in multipledirections on a series of slices can be performed so as to create athree-dimensional representation of the area of interest. By detectingthe position of the renal arteries from more than one angle via Dopplertriangulation (for example) or another triangulation technique, a threedimensional positional map can be created and the renal artery can bemapped into a coordinate reference frame. In this respect, given thatthe renal nerves surround the renal blood vessels in the hilum, locatingthe direction and lengths of the blood vessels in three dimensionalcoordinate reference is the predominant component of the procedure totarget these sympathetic nerves. Within the three dimensional referenceframe, a pattern of energy can be applied to the vicinity of the renalartery from a device well outside the vicinity (and outside of thepatient altogether) based on knowledge of the coordinate referenceframe.

For example, once the renal artery is placed in the coordinate referenceframe with the origin of the energy delivery device, an algorithm isutilized to localize the delivery of focused ultrasound to heat or applymechanical energy to the adventitia and surrounding regions of theartery which contain sympathetic nerves to the kidney and afferentnerves from the kidney, thereby decreasing the sympathetic stimulus tothe kidney and decreasing its afferent signaling back to the autonomicnervous system; affecting these targets will modulate the propensitytoward hypertension which would otherwise occur. The ultrasonic energydelivery can be modeled mathematically by predicting the acoustic wavedissipation using the distances and measurements taken with the imagingmodalities of the tissues and path lengths. Furthermore, a system suchas acoustic time of flight can be utilized to quantitatively determinethe distance from a position on the therapeutic transducer to the regionof the blood vessel to the kidney. Such a system allows for detection ofa distance using an ultrasound pulse. The distance obtained as such isthen utilized for the therapeutic ultrasound treatment because thetissues and structures which are interrogated are the same ones throughwhich the therapeutic ultrasound will travel, thereby allowingessentially auto-calibration of the therapeutic ultrasound pulse.

For example, FIG. 1D depicts a system with an integral catheter 652 andone or more transducers 654 on the catheter. Electrical impulses aresent from a generator 653 to the catheter 652 and to the transducers 654which may be piezoelectric crystals. Detectors 650 detect the distance656 from the piezoelectric transducers as well as the 3-dimensionalorientation and exact position of the transducers 654. With positionalinformation in three dimensional space, focused ultrasound transducer662 can be directed toward the target under the direction of motioncontrollers/transducer(s) 660. In some embodiments, a single transducer(internal) is detected. In other embodiments, multiple transducers 654are detected. In the embodiment in which multiple transducers areutilized, more detail around the three dimensional position andorientation of the vessel is available allowing for a redundant approachto position detection. In either case, by pulling back the catheterwithin the blood vessel while applying electrical signals to thepiezoelectric crystal so that they may be detected outside the patient,the three dimensional anatomy of the vessel can be mapped and determinedquantitatively so that treatment can be applied at an exact locationalong the blood vessel. In this method, a guidewire is placed at thesite of treatment and then moved to different positions close to thetreatment site (e.g. within a blood vessel). During the movement alongthe blood vessel, the detectors outside the patient are mapping themovement and the region of treatment. The map of the blood vessel (forexample) is then used to perform the treatment in the exact regionplanned with a high degree of accuracy due to the mapping of the region.Signal generator 653 may create signals with frequencies ranging from0.5 MHz up to 3 MHz (or any frequency value in this range), or even awider range of frequencies to ensure detection of the orientation.

In one embodiment of an algorithm, the Doppler signal from the artery isidentified from at least two different directions and the direction ofthe artery is reconstructed in three dimensional space. In this example,acoustic time of flight may be utilized via the Doppler ultrasound ofthe flow signal, or via a piezoelectric transducer (internal) andreceiver (external) 650 set up. With two points in space, a line iscreated and with knowledge of the thickness of the vessel, a tube, orcylinder, can be created to represent the blood vessel as a virtualmodel. The tube is represented in three dimensional space over time andits coordinates are known relative to the therapeutic transducersoutside of the skin of the patient. Therapeutic energy can be appliedfrom more than one direction as well and can focus on the cylinder(blood anterior vessel wall, central axis, or posterior wall). With athird point, the position of the target can be precisely localized inthe 3D space and targeted with a HIFU transducer 660. Position detectionalgorithm 666 can be utilized to compare the baseline position of thecatheter to a position after a period of time so as to detectrespiratory and patient movement. In one embodiment, the therapeuticHIFU array 662 is also used to send a signal out for imaging (diagnosticpulse). For example, any number of elements can be activated from theHIFU array to deposit energy into the tissue. Such energy deposition canbe advantageous because it is by definition focused on the region 664that will ultimately be treated. In this respect, the exact region oftreatment can be interrogated with the focused ultrasound pulse from thetherapeutic array 662. Parameters in addition to imagining includeDoppler flow, tissue elastography, stress strain curves, ultrasoundspectroscopy, and targeting of therapeutics to the region. Thetherapeutic array 662 can be utilized as a receiver for the diagnosticsignal or a separate detector can be utilized as the receiver. In someembodiments, the catheter may be adapted to deliver pharmaceuticals tothe region as well as to assist in beam focusing. A Doppler targetingalgorithm may complement the catheter 652 based targeting. Power supplyis configured to apply the proper power to the HIFU transducer to treata blood vessel deep within a patient. For example, the power input intothe HIFU transducer might be 150 W, 200 W, 500 W 750 W, or 1000 W toachieve output suitable for deep treatment in a patient. Pulsingfrequency may be as fast as 10 Hz or even 1 KHz. The piezoelectricsignal may be detected from more than one direction outside the body ofthe patient. One or more modes of ultrasound may be utilized anddetected from different directions outside the skin of the patient. Verylarge impulses may be generated in the first few microseconds of thepiezoelectric impulse delivery. For example, in some embodiments, 8W/Cm2 may be generated for a few microseconds and then the voltage maybe quickly decreased to zero until the next cycle (<1% duty cycle).

Focused energy (e.g. ultrasound) can be applied to the center of thevessel (within the flow), on the posterior wall of the vessel, inbetween (e.g. when there is a back to back artery and vein next to oneanother) the artery vessel and a venous vessel, etc. Mover 660 directsthe ultrasound focus based on position 666 of the catheter 652 relativeto the ultrasound array 660. In some embodiments, a Doppler signal 670is used with/combined in the system.

Imaging 600 (FIG. 1C) of the sympathetic nerves or the sympatheticregion (the target) is also utilized so as to assess the direction andorientation of the transducers relative to the target 620; the target isan internal fiducial, which in one embodiment is the kidney 610 andassociated renal artery 620 because they can be localized via theirblood flow, a model then produced around it, and then they both can beused as a target for the energy. Continuous feedback of the position ofthe transducers 500, 510 relative to the target 620 is provided by theimaging system, wherein the position may be in the coordinate space ofthe imaging system, for example. The imaging may be a cross-sectionalimaging technology such as CT or MRI or it may be an ultrasound imagingtechnology which yields faster real time imaging. In some embodiments,the imaging may be a combination of technologies such as the fusion ofMRI/CT and ultrasound. The imaging system can detect the position of thetarget in real time at frequencies ranging from 1 Hz to thousands andtens of thousands of images per second.

In the example of fusion, cross-sectional imaging (e.g. MRI/CT) isutilized to place the body of the patient in a three dimensionalcoordinate frame and then ultrasound is linked to the three dimensionalreference frame and utilized to track the patient's body in real timeunder the ultrasound linked to the cross-sectional imaging. The lack ofresolution provided by the ultrasound is made up for by thecross-sectional imaging since only a few consistent anatomic landmarksare required for an ultrasound image to be linked to the MRI image. Asthe body moves under the ultrasound, the progressively new ultrasoundimages are linked to the MRI images and therefore MRI “movement” can beseen at a frequency not otherwise available to an MRI series.

In one embodiment, ultrasound is the energy used to inhibit nerveconduction in the sympathetic nerves. In one embodiment, focusedultrasound (HIFU) from outside the body through the skin is the energyused to inhibit sympathetic stimulation of the kidney by deliveringwaves from a position external to the body of a patient and focusing thewaves on the sympathetic nerves on the inside of the patient and whichsurround the renal artery of the patient. MRI may be used to visualizethe region of treatment either before, during, or after application ofthe ultrasound. MRI may also be used to heat a targeting catheter in theregion of the sympathetic nerves. For example, a ferromagnetic elementon the tip of a catheter will absorb energy in the presence of amagnetic field and heat itself, thereby enabling heat to be applied tothe nerves surrounding the blood vessels leading to the kidney.

FIG. 1E depicts an overview of the software subsystems 675 to deliver asafe treatment to a patient. An executive control system 677 contains anoperating system, a recording of the system functions, a networkconnection, and other diagnostic equipment. Communication with treatmentdosimetry plan 681 may be accomplished via modeling and previouslyobtained empirical data. The software within the dosimetry plan allowsfor further communication with the acoustic time of flight transducer(ATOF) 679 and the motion controller for the diagnostic and therapeuticarrays. Target localization based on acoustic time of flight (ATOF) canprovide accurate and robust position sensing of target location relativeto the therapeutic ultrasound transducer. Direct X, Y and Z (i.e.three-dimensional) coordinate locations of the target can be providedwithout the need for image interpretation. Three-dimensional targetinginformation facilitates the use of an explicit user interface to guideoperator actions. ATOF is less sensitive to variations in patientanatomy as compared to imaging techniques. ATOF can be accomplished witha relatively simple and inexpensive system compared to the compleximaging systems used by alternate techniques. In some embodiments,continuous tracking of the target in the presence of movement betweenthe target and the external transducer may be provided. In someembodiments, ATOF allows use of system architectures that utilize alarger fraction of the patient contact area to generate therapeuticpower (as contrasted with imaging based alternatives which occupy somespace within the therapeutic transducer for diagnostic power)—thusreducing the power density applied to the patient's skin.

As is depicted in FIG. 3 a-b, transducers 900 can emit ultrasound energyfrom a position outside the patient to the region of the renalsympathetic nerves at the renal pedicle 200. As shown in FIG. 1 a, animage of the renal artery 620 using an ultrasound, MRI, or CT scan canbe utilized to determine the position of the kidney 610 and the renalartery 620 target. Doppler ultrasound can be used to determine thelocation and direction of a Doppler signal from an artery and place thevessel into a three dimensional reference frame 950, thereby enablingthe arteries 200 and hence the sympathetic nerves 220 (FIG. 3 a) aroundthe artery to be much more visible so as to process the images and thenutilize focused external energy to pinpoint the location and therapy ofthe sympathetic nerves. In this embodiment, ultrasound is likely themost appropriate imaging modality. Ultrasound can refer to simple singledimensional pulse echos, or devices which scan a region and integratepulse echos into an image (termed B-mode).

FIG. 1A also depicts the delivery of focused energy to the sympatheticnerve trunks and ganglia 622 which run along the vertebral column andaorta 300; the renal artery efferent nerves travel in these trunks andsynapse to ganglia within the trunks. In another embodiment, ablation ofthe dorsal and ventral roots at the level of the ganglia or dorsal rootnerves at T9-T11 (through which the afferent renal nerves travel) wouldproduce the same or similar effect to ablation at the level of the renalarteries.

In another embodiment, FIG. 1B illustrates the application of ionizingenergy to the region of the sympathetic nerves on the renal arteries 620and/or renal veins. In general, energy levels of greater than 20 Gy(Gray) are required for linear accelerators or low energy x-ray machinesto ablate nervous tissue using ionizing energy; however, lower energy isrequired to stun, inhibit nervous tissue, or prevent re-growth ofnervous tissue; in some embodiment, ionizing energy levels as low as 2-5Gy or 5-10 Gy or 10-15 Gy are delivered in a single or fractionateddoses. Ionizing energy can be applied using an orthovoltage X-raygenerator, a linear accelerator, brachytherapy, and/or an intravascularX-ray radiator which delivers electronic brachytherapy. X-rays such asfrom a linear accelerator or from an orthovoltage x-ray generator can bedelivered through the skin from multiple directions to target nervessurrounding a blood vessel. In one example, the blood vessel might be arenal artery or renal vein with nerves running around it. By targetingthe blood vessel, ionizing energy can be applied to the nervessurrounding the blood vessel. Ultrasound, Doppler imaging, angiograms,fluoroscopy, CT scans, thermography imaging, and MRIs can be utilized todirect the ionizing energy.

Combinations of ionizing energy and other forms of energy can beutilized in this embodiment as well so as to prevent re-growth of thenervous tissue. For example, a combination of heat and/or vibrationand/or cavitation and/or ionizing radiation might be utilized to preventre-growth of nervous tissue after the partial or full ablation of thenervous tissue surrounding the renal artery. Combinations ofpharmaceutical agents can be combined with one another or with deviceand physical means to prevent or initially inhibit nerve tissue and/orregrowth of nerve tissue.

FIG. 2 illustrates the renal anatomy and surrounding anatomy withgreater detail in that organs such as the stomach 700 are shown in itsanatomic position overlying the abdominal aorta 705 and renal arteries715. In this embodiment, energy is delivered through the stomach toreach an area behind the stomach. In this embodiment, the stomach isutilized as a conduit to access the celiac ganglion 710, a region whichwould otherwise be difficult to reach. The aorta 705 is shown underneaththe stomach and the celiac ganglion 710 is depicted surrounding thesuperior mesenteric artery and aorta. A transorally placed tube 720 isplaced through the esophagus and into the stomach. The tube overlies theceliac ganglion when placed in the stomach and can therefore be used todeliver sympatholytic devices or pharmaceuticals which inhibit orstimulate the autonomic celiac ganglia behind the stomach; thesetherapies would be delivered via transabdominal ultrasound orfluoroscopic guidance (for imaging) through the stomach. Similartherapies can be delivered to the inferior mesenteric ganglion, renalnerves, or sympathetic nerves traveling along the aorta through thestomach or other portion of the gastrointestinal tract. The energydelivery transducers 730 are depicted external to the patient and can beutilized to augment the therapy being delivered through the stomach tothe celiac ganglion. Alternatively, the energy delivery transducers canbe utilized for imaging the region of therapy. For example, anultrasound transducer can be utilized to image the aorta and celiacganglion and subsequently to apply ultrasound energy to the region toinhibit the nerves in the region. In some cases, ablation is utilizedand in other cases, vibration is utilized to inhibit the nerves fromfunctioning.

In one embodiment, energy is applied to the region of the celiacganglion from a region outside the patient. In this embodiment, fluid isplaced into the gastrointestinal system, such as for example, in thestomach or small intestine. Ultrasound can then be transmitted throughthe gastrointestinal organs to the ganglia of interest behind thestomach.

Temporary neurostimulators can also be placed through the tube placedinto the esophagus and into the stomach, such as, for example, in an ICUsetting where temporary blockage of the autonomic ganglia may berequired. Temporary neurostimulators can be used to over pace the celiacganglion nerve fibers and inhibit their function as a nerve synapse.Inhibition of the celiac ganglion may achieve a similar function asablation or modulation of the sympathetic nerves around the renalarteries. That is, the decrease in the sympathetic activity to thekidneys (now obtained with a more proximal inhibition) leads to thelowering of blood pressure in the patient by decreasing the degree ofsympathetic outflow from the sympathetic nerve terminals. In the celiacganglia, the blood pressure lowering effect is more profound given thatthe celiac ganglia are pre-ganglionic and have more nerve fibers to agreater number of regions than each renal nerve. The effect is alsolikely more permanent than the effect on the post-ganglionic nervefibers.

FIG. 3A illustrates the renal anatomy more specifically in that therenal nerves 220 extending longitudinally along the renal artery 200,are located generally within, or just outside the adventitia, of theouter portion of the artery. Arteries are typically composed of threelayers: the first is the intimal, the second is the media, and the thirdis the adventitia. The outer layer, the adventitia, is a fibrous tissuewhich contains blood vessels and nerves. The renal nerves are generallypostganglionic sympathetic nerves although there are some ganglia whichexist distal to the takeoff from the aorta such that some of the nervefibers along the renal artery are in fact pre-ganglionic. By the timethe fibers reach the kidney, the majority of the fibers arepost-ganglionic. The afferent nerves on the other hand leave the kidneyand are post-ganglionic up to the level of the brain. These fibers donot re-grow as quickly as the efferent fibers, if at all.

Energy generators 900 deliver energy to the renal nerves accompanyingthe renal artery, depositing energy from multiple directions to targetinhibition of the renal nerve complex. The energy generators can deliverultrasound energy, ionizing radiation, light (photon) therapy, ormicrowave energy to the region. The energy can be non-focused in thecase where a pharmaceutical agent is targeted to the region to beablated or modulated. Preferably, however, the energy is focused, beingapplied from multiple angles from outside the body of the patient toreach the region of interest (e.g. sympathetic nerves surrounding bloodvessels). The energy transducers 900 are placed in an X-Y-Z coordinatereference frame 950, as are the organs such as the kidneys. The x-y-zcoordinate frame is a real space coordinate frame. For example, realspace means that the coordinate reference is identifiable in thephysical world; like a GPS (global positioning system), with thephysical coordinates, a physical object can be located. Once in thex-y-z coordinate reference frame, cross-sectional imaging using MRI, CTscan, and/or ultrasound is utilized to couple the internal anatomy tothe energy transducers. These same transducers may be utilized for thedetermination of the reference point as well as the therapy. Thetransducers 900 in this embodiment are focused on the region of therenal nerves at the level of the renal blood vessels, the arteries andveins 200. The focus of the beams can be inside the artery, inside thevein, on the adventitia of the artery or adventitia of the vein.

When applying ultrasonic energy across the skin to the renal arteryregion, energy densities of potentially over 1 MW/cm² might be requiredat region of interest in the adventitia of the blood vessel. Typically,however, power densities of 100 W/cm² to 3 kW/cm² would be expected tocreate the heating required to inhibit these nerves (see Foley et. al.Image-Guided HIFU Neurolysis of Peripheral Nerves To Treat SpasticityAnd Pain; Ultrasound in Med & Biol. Vol 30 (9) p 1199-1207). The energymay be pulsed across the skin in an unfocused manner; however, forapplication of heat, the transducers must be focused otherwise the skinand underlying tissues will receive too much heat. Under imaging withMRI, temperature can be measured with the MRI image. When low energyultrasound is applied to the region, energy (power) densities in therange of 50 mW/cm² to 500 mW/cm² may be applied. Low energy ultrasoundmay be enough to stun or partially inhibit the renal nerves particularlywhen pulsed and depending on the desired clinical result. High intensityultrasound applied to the region with only a few degrees of temperaturerise may have the same effect and this energy range may be in the 0.1kW/cm2 to the 500 kW/cm2 range. A train of pulses also might be utilizedto augment the effect on nervous tissue. For example, a train of 100short pulses, each less than a second and applying energy densities of 1W/cm² to 500 W/cm². In some of the embodiments, cooling may be appliedto the skin if the temperature rise is deemed too large to beacceptable. In some embodiments, infrared thermography is utilized todetermine the temperature of the skin and subcutaneous tissues, or ifdetected from deeper within, from the kidneys and even renal bloodvessels themselves. Alternatively, the ultrasound transducers can bepulsed or can be alternated with another set of transducers toeffectively spread the heat across the surface of the skin. In someembodiments, the energy is delivered in a pulsed fashion to furtherdecrease the risk to the intervening tissues between the target and thetransducer. The pulses can be as close as millisecond, as described, oras long as hours, days or years.

In one method of altering the physiologic process of renal sympatheticexcitation, the region around the renal arteries is imaged using CTscan, MRI, thermography, infrared imaging, optical coherence tomography(OCT), photoacoustic imaging, pet imaging, SPECT imaging, or ultrasound,and the images are placed into a three dimensional coordinate referenceframe 950. The coordinate reference frame 950 refers to the knowledge ofthe relationship between anatomic structures, both two dimensional andthree dimensional, the structures placed into a physical coordinatereference. Imaging devices determine the coordinate frame. Once thecoordinate frame is established, the imaging and therapy transducers 900can be coupled such that the information from the imaging system isutilized by the therapeutic transducers to position the energy. Bloodvessels may provide a useful reference frame for deposition of energy asthey have a unique imaging signature. An ultrasound pulse echo canprovide a Doppler shift signature to identify the blood vessel from thesurrounding tissue. In an MRI, CT scan, and even an ultrasound exam,intravenous contrast agents can be utilized to identify flow patternsuseful to determine a coordinate reference for energy deposition. Energytransducers 900 which can deliver ultrasound, light, radiation, ionizingradiation, or microwave energy are placed in the same three-dimensionalreference frame as the renal arteries, at which time a processor (e.g.using an algorithm) can determine how to direct the transducers todeliver energy to the region 220 of the nerves 910. The algorithmconsists of a targeting feature (planning feature) which allows forprediction of the position and energy deposition of the energy leavingthe transducers 900.

Once the three dimensional coordinate reference frames 950 are linked orcoupled, the planning and prediction algorithm can be used to preciselyposition the energy beams at a target in the body.

The original imaging modality can be utilized to locate the renalsympathetic region, and/or can be used to track the motion of the regionduring treatment. For example, the imaging technology used at time zerois taken as the baseline scan and subsequent scans at time t1 arecompared to the baseline scan, t0 (start). The frequency of updates canrange from a single scan every few seconds to many scans per second.With ultrasound as the imaging technology, the location might be updatedat a frame rate greater than 50 Hz and up to several hundred Hz orthousand Hz. With MRI as the imaging modality, the imaging refresh ratemight be closer to 30 Hz. In other embodiments, internally placedfiducials transmit positional information at a high frequency and thisinformation is utilized to fuse the target with an initial externalimaging apparatus. Internal fiducials might include one or moreimageable elements including doppler signals, regions of blood vessels,ribs, kidneys, and blood vessels and organs other than the target (e.g.vena cava, adrenal gland, ureter). These fiducials can be used to trackthe region being treated and/or to triangulate to the region to betreated. The fiducials can be placed externally to an internal positionor might be intrinsic fiducials such as anatomic features and/orimageable features.

In some embodiments (FIG. 3C), a temporary fiducial 960 is placed in theregion, such as in the artery 965, renal vein 975, aorta 945, and/orvena cava 985; such a fiducial is easily imageable from outside thepatient. In one embodiment, the temporary fiducial may enhance imagingsuch as a balloon fillable with gas or bubbles. In another embodiment,the temporary fiducial may be a material imageable via MRI orultrasound.

FIG. 3D depicts an imageable transducer 960 in a blood vessel 967 withina coordinate reference 975 on a monitor system 950. Alternatively, thetemporary fiducial 960 is a transducer which further improves theability to image and track the region to deliver therapy. The transducermay be a piezoelectric crystal which is stimulated to emit energy whichcan be detected by one or more detectors to determine a threedimensional position. The transducer may release radiofrequency energywhich can be detected by one or more detectors to pinpoint a threedimensional position. The transducer may emit an audible sound or anoptical signal. The temporary fiducial might be a mechanical, optical,electromechanical, a radiofrequency radiotransmitter, an ultrasoundgenerator, a global positioning tracking (GPS) device, or ultrasoundresponsive technology. Similar devices that may be used to assist inperforming the treatment described herein might be found in U.S. Pat.Nos. 6,656,131 and 7,470,241 which are incorporated by reference herein.

Internal reflections (e.g. speckles) can be tracked as well. Thesespeckles are inherent characteristics of tissue as imaged withultrasound. They can be tracked and incorporated into treatment planningalgorithm and then linked to the therapeutic transducers. In someembodiments, cavitation is detected, in which vapor bubbles are detectedto determine temperature or degree of heating.

In some embodiments, a test dose of energy can be applied to the renalsympathetic region and then a test performed to determine if an effectwas created. For example, a small amount of heat or vibratory energy canbe delivered to the region of the sympathetic nerves and then a test ofsympathetic activity such as microneurography (detection of sympatheticnerve activity around muscles and nerves which correlate with thebeating heart) can be performed. Past research and current clinical datahave shown that the sympathetic nerves to the peripheral muscles areaffected by interruption of the renal afferent nerves. The degree oftemperature rise with the small degree of heat can be determined throughthe use of MRI thermometry or an ultrasound technique and thetemperature rise can be determined or limited to an amount which isreversible.

In another embodiment, a stimulus is applied to a region such as theskin and an output downstream from the skin is detected. For example, avibratory energy might be applied to the skin and a sympathetic outflowsuch as the heart rate might be detected. In another embodiment, heat orcold might be applied to the skin and heart rate, blood pressure;vasoconstriction might be detected as an output.

Alternatively, ultrasonic imaging can be utilized to determine theapproximate temperature rise of the tissue region. The speed ofultrasonic waves is dependent on temperature and therefore the relativespeed of the ultrasound transmission from a region being heated willdepend on the temperature, therefore providing measureable variables tomonitor. In some embodiments, microbubbles are utilized to determine therise in temperature. Microbubbles expand and then degrade when exposedto increasing temperature so that they can then predict the temperatureof the region being heated. The microbubbles can be injected into thevein or artery of a patient or the microbubbles can be injected locallyinto the aorta, renal artery, renal vein, etc. A technique calledultrasound elastography can also be utilized. In this embodiment, theelastic properties of tissue are dependent on temperature and thereforethe elastography may be utilized to track features of temperaturechange. The microbubbles can also be utilized to augment the therapeuticeffect of the region being targeted. For example, the microbubbles canbe utilized to release a pharmaceutical when the ultrasound reachesthem. Alternatively, the microbubble structure can be utilized toenhance imaging of the treatment region to improve targeting or trackingof the treatment region.

In some embodiments, only the temperature determination is utilized.That is, the temperature sensing embodiments and algorithms describedherein are utilized with any procedure in which heating is beingperformed. For example, in a case where heating of the renal nerveregion is performed using radiofrequency ablation through the renalartery, imaging of the region from a position external to the patientcan be performed while the renal artery region is being heated viaradiofrequency methods. Imaging can be accomplished utilizing MRI,ultrasound, infrared, or OCT methods. Imaging can be utilized todetermine temperature or an effect of temperature on the regionssurrounding the blood vessel and/or nerves. For example, aradiofrequency catheter can be utilized to apply energy to the wall of ablood vessel and then ultrasound imaging can be applied during or afterthe treatment with the radiofrequency catheter, at which pointtemperature, coagulation status, and nerve damage can be determinedaround the blood vessel with the nerve. In addition or alternatively,MRI can be utilized to determine temperature or map effect on the nervestructures surrounding the blood vessels.

Such imaging of the treatment can assist in the directing precisetreatment to the region around the blood vessel, and allow for safeapplication of heat to the blood vessel wall. For example, in oneembodiment, energy is applied to the wall of the blood vessel and theheat is detected during the treatment. The temperature in such anembodiment can be limited with a specified level (e.g. 55 degrees, 60degrees, 65 degrees) for a specific amount of time (e.g. 30 seconds, 60seconds, 120 seconds). MRI or ultrasound or both can be used for thistreatment. In this method the localization of the heat about the wall ofthe blood vessel can be determined.

In another embodiment, a test may be performed on the baroreceptorcomplex at the region of the carotid artery bifurcation. After the testdose of energy is applied to the renal artery complex, pressure can beapplied to the carotid artery complex; typically, with an intactbaroreceptor complex, the systemic blood pressure would decrease afterapplication of pressure to the carotid artery. However, with renalafferent nerves which have been inhibited, the baroreceptors will not besensitive to changes in blood pressure and therefore the efficacy of theapplication of the energy to the renal nerves can be determined. Othertests include attaining indices of autonomic function such asmicroneurography, autonomic function variability, etc.

In another embodiment, stimulation of the baroreceptor complex isaccomplished non-invasively via ultrasound pulses applied externally tothe region of the carotid body. The ultrasound pulses are sufficient tostimulate the sinus to affect a blood pressure change, a change whichwill be affected when an afferent nerve such as the renal afferents havebeen altered.

More specifically, this methodology is depicted in FIG. 3E. Anultrasound pulse 980 is utilized to stimulate the carotid sinus whichwill lower blood pressure transiently 982 by activating the baroreceptorcomplex; activation of the carotid sinus 980 simulates the effect of anincrease in blood pressure which leads to a compensatory outflow ofparasympathetic activity and decreased sympathetic outflow, subsequentlylowering blood pressure. In the instance when the afferent system (e.g.from the kidney) has been inhibited, the pressure will not be modifiableas quickly if at all. In this case, stimulating the baroreceptor complexdoes not result in a lowering of blood pressure 986, then the treatmentwas successful. This diagnostic technique can therefore be utilized todetermine the effect of a therapy on a system such as the renal nervecomplex. If therapy is successful, then the modifying effect of theultrasound pulse on the carotid sinus and blood pressure is lessdramatic and the therapeutic (treatment of afferent nerves) successful;therefore, therapy can be discontinued 988 temporarily or permanently.If the blood pressure continues to decrease 982 with the baroreceptorstimulation, then the therapeutic effect has not been reached with thetherapeutic treatment and it needs to be continued 984 and/or the doseincreased. Other methods to stimulate the baroreceptor complex are toapply pressure in the vicinity with hands, compression balloons,electrical stimulators, and the like.

Other regions of the autonomic nervous system can also be affecteddirectly by the technology described herein by applying energy from oneregion and transmitted through tissue to another region. For example,FIG. 4A illustrates a system in which energy external to the internalcarotid artery is applied to a portion of the autonomic nervous system,the carotid body complex 1000, through the internal jugular vein 1005,and to the carotid body 1000 and/or vagus nerve region 1022, and/orvertebral artery 1015. Ablative energy, vibratory, or electricalstimulation energy can be utilized to affect the transmission of signalsto and from these nerves. The transmission in this complex can beaugmented, interrupted, inhibited with over-stimulation, or acombination of these effects via energy (e.g. ultrasound, electricalstimulation, etc.).

In addition, or in place of, in other embodiments, energy may be appliedto peripheral nerves typically known as motor nerves but which containautonomic fibers. Such nerves include the saphenous nerve, femoralnerves, lumbar nerves, median nerves, ulnar nerves, and radial nerves.In some embodiments, energy is applied to the nerves and specificautonomic fibers are affected rather than the other neural fibers (e.g.motor or somatic sensory fibers or efferent or afferent autonomicnerves). In some embodiments, other types of autonomic fibers areaffected with energy applied internally or externally. For example,nerves surrounding the superior mesenteric artery, the inferiormesenteric artery, the femoral artery, the pelvic arteries, the portalvein, hepatic artery, pulmonary arteries, pulmonary veins, aorta, venacava, etc. can be affected by the energy in a specific manner so as tocreate changes in the autonomic responses of the blood vesselsthemselves or organs related to the blood vessels, the nerves runningthrough and along the vessels to the organs.

In another embodiment, in FIG. 4 a, a catheter 1010 is advanced into theinternal jugular vein 1005 and when in position, stimulation or ablativeenergy 1020 is directed toward the autonomic nerves, e.g. the vagusnerve and the carotid sinus/body 1000, from the catheter positioned inthe venous system 1005.

In a similar type of embodiment 1100, a catheter based therapeuticenergy source 1110 can be inserted into the region of the renal arteriesor renal veins (FIG. 4B) to stimulate or inhibit the renal nerves fromthe inside of the vessel, either the renal artery 1105 or renal vein1106. Energy is transferred through the vessel (e.g. renal vein) toreach the nerves around another vessel (e.g. renal artery). For example,a catheter delivering unfocused ultrasound energy with powers in therange of 50 mW/cm² to 50 kW/cm² can be placed into the renal artery andthe energy transmitted radially around the artery or vein to thesurrounding nerves. As discussed below, the 500 mW-2500 W/cm² isappropriate to create the specific nerve dysfunction to affect thenorepinephrine levels in the kidney, a surrogate of nerve function whichhas been shown to lead to decreases in blood pressure over time. Pulsedultrasound, for example, 100 pulse trains with each lasting less than 1second each, can be applied to the region.

In an exemplary embodiment, the tubular body 1105 is elongate andflexible, and comprises an outer sheath that is positioned over an innercore. For example, in embodiments particularly well-suited for the renalblood vessels, the outer sheath 108 can comprise extrudedpolytetrafluoroethylene (“PTFE”), polyetheretherketone (“PEEK”),polyethylene (“PE”), polyamides, braided polyamides and/or other similarmaterials. In such embodiments, the outer sheath 108 has an outerdiameter of approximately 0.039 inch (0.039 inch±0.01 inch) at itsproximal end and between approximately 0.033 inch (0.033 inch±0.01 inch)and approximately 0.039 inch (0.039 inch±0.01 inch) at its distal end.In such embodiments, the outer sheath 108 has an axial length ofapproximately 150 centimeters (150 cm±20 cm). In other embodiments, theouter sheath 108 can be formed from a braided tubing comprising high orlow density polyethylenes, urethanes, nylons, and so forth. Suchconfigurations enhance the flexibility of the tubular body 1105. Instill other embodiments, the outer sheath can include a stiffeningmember (not shown) at the tubular body proximal end.

The inner core at least partially defines a central lumen, or “guidewirelumen,” which preferably extends through the length of the catheter. Thecentral lumen has a distal exit port and a proximal access port. In someembodiments, the proximal portion of the catheter is defined by atherapeutic compound inlet port on a back end hub, which is attachedproximally. In the exemplary embodiment the back end hub is attached toa control box connector, which is described in greater detail below.

In an exemplary embodiment, the central lumen is configured to receive aguidewire (not shown) having a diameter of between approximately 0.010inch (0.01 inch±0.005 inch) to approximately 0.012 inch (0.012inch±0.005 inch). In an exemplary embodiment, the inner core is formedfrom polymide or a similar material, which can optionally be braided toincrease the flexibility of the tubular body 1105.

Referring now to an exemplary embodiment illustrated in FIG. 4B, thedistal end of the tubular body includes an ultrasound radiating member1110. In the illustrated embodiment, the ultrasound radiating member1110 comprises an ultrasonic transducer, which converts, for example,electrical energy into ultrasonic energy.

An inner core extends through the ultrasound radiating member, which ispositioned over the inner core. The ultrasound radiating member can besecured to the inner core in a suitable manner, such as with anadhesive. Extending the core through the member advantageously providesenhanced cooling of the ultrasound radiating member. A therapeuticcompound can be injected through a central lumen, thereby providing aheat sink for heat generated by the ultrasound radiating member. Thetherapeutic compound can enhance the effect of the ultrasound on thenerves surrounding the blood vessel.

Suitable operating frequencies for the ultrasound radiating memberinclude, but are not limited to, from about 20 kHz (20 kHz±2 kHz) toless than about 20 MHz (20 MHz±2 MHz). In one embodiment, the frequencyis between 500 kHz and about 20 MHz (20 MHz±2 MHz), and in anotherembodiment the frequency is between about 1 MHz (1 MHz±0.1 MHz) andabout 3 MHz (3 MHz±0.3 MHz). In yet another embodiment, the ultrasonicenergy has a frequency of about 3 MHz (3 MHz±0.3 MHz).

In another embodiment, light is applied through the vessel from withinthe blood vessel. Infrared, red, blue, and near infrared can all beutilized to affect the function of nerves surrounding blood vessels. Forexample, a light source is introduced into the renal artery or renalvein 1105, 1106 and the light transmitted to the region surrounding theblood vessels. In a preferred embodiment, a photosensitizing agent isutilized to hasten the inhibition or destruction of the nerve bundleswith this technique. Photosensitizing agents can be applied systemicallyto infiltrate the region around the blood vessels. Light is then appliedfrom inside the vessel to the region of the nerves outside the vessel.For example, the light source is placed inside the renal vein and thenlight is transmitted through the vein wall to the adventitial regionaround the wall activating the photosensitizer and injuring orinhibiting the nerves in the adventitia through an apoptosis pathway.The light source may provide light that is visible, or light that isnon-visible. In another embodiment, the light is applied to the regionwithout photosensitizer. The light generates heat in the region throughabsorption of the light. Wavelengths such as those in the red,near-infrared, and infrared region are absorbed by the tissues aroundthe artery and leads to destruction of the nerves in the region.

In one embodiment, a string of light emitting diodes (LEDs) is fed intothe blood vessel and the vessel illuminated with light from inside thevessel. Lights that are near infrared and infrared have good penetrationin blood and through tissues and can be utilized to heat or activatepharmaceuticals in the region surrounding the blood vessel leading tothe kidney. These light frequency devices and energies can be utilizedto visualize the inside and/or outside of the blood vessel.Intravascular OCT might be utilized to visualize damage to the nervessurrounding the blood vessels.

The therapies in FIGS. 4A-B can be delivered on an acute basis such asfor example in an ICU or critical care setting. In such a case, thetherapy would be acute and intermittent, with the source outside thepatient and the catheter within the patient as shown in FIGS. 4 a-b. Thetherapy can be utilized during times of stress for the patient such thatthe sympathetic system is slowed down. After the intensive careadmission is nearing a close, the catheter and unit can be removed fromthe patient. In one embodiment, a method is described in which acatheter is placed within a patient to deliver energy to a region of thebody sufficient to partially or fully inhibit an autonomic nerve complexduring a state of profound sympathetic activation such as shock, sepsis,myocardial infarction, pancreatitis, post-surgical. After the acutephase of implantation during which the sympathetic system is modulated,the device is removed entirely.

FIGS. 5A-B illustrates the eye in close up detail with sympatheticnerves surrounding the posterior of the eye. In the eye, glaucoma is aproblem of world-wide importance. The most commonly prescribedmedication to treat glaucoma is timoptic, which is a non-selective β1and β2 (adrenergic) antagonist. Compliance with this pharmaceutical is amajor problem and limits its effectiveness in preventing thecomplications of glaucoma, the major complication being progression ofvisual dysfunction.

Ultrasound, or other energy transducers 7000, can be applied to focusenergy from an external region (e.g. a distance from the eye in anexternal location) anterior to the eye or to a region posteriorly behindthe eye 2500 on the sympathetic 2010 or parasympathetic ganglia, all ofwhich will affect lowering of intra-ocular pressure. The energytransducers 7000 apply ablative or near ablative energy to theadventitia of the blood vessels. In some embodiments, the energy is notablative but vibratory at frequencies (e.g. 1-5 Mhz) and penetrationdepths (e.g. 0.5 mm to 0.5 cm) sufficient to inhibit the function of thenerves which are responsible for intra-ocular pressure. Lower energy(e.g. sub-ablative) can be applied to the eye to assist in drug deliveryor to stimulate tissue healing type of tissue responses.

FIG. 5B depicts the anatomy of the nerves which travel behind the eye2500. In this illustration, a catheter 2000 is tunneled through thevasculature to the region of the sympathetic nerves surrounding thearteries of the eye 2010 and utilized to ablate, stun, or otherwisemodulate the efferent and/or afferent nerves through the wall of thevasculature leading to the eye.

FIG. 6 illustrates an overall schematic of the renal artery, renal vein,the collecting system, and the more distal vessels and collecting systemwithin the renal parenchyma. The individual nerves of the autonomicnervous system typically follow the body vasculature and they are shownin close proximity 3000 to the renal artery as the artery enters thekidney 3100 proper. The hilum of the kidney contains pressure sensorsand chemical sensors which influence the inputs to the efferentsympathetic system via afferent nerves traveling from the kidney to thecentral nervous system and then to the efferent nervous system. Any oneor multiple of these structures can influence the function of thekidney. Ablative or non-ablative energy can be applied to the renalvein, the renal artery, the aorta, and/or the vena cava, the renalhilum, the renal parenchyma, the renal medulla, the renal cortex, etc.

In another embodiment, selective lesions, constrictions or implants 3200are placed in the calyces of the kidney to control or impede blood flowto specific regions of the kidney. Such lesions or implants can beplaced on the arterial 3010 or venous sides 3220 of the kidney. In someembodiments, the lesions/implants are created so as to selectively blockcertain portions of the sympathetic nerves within the kidney. Thelesions also may be positioned so as to ablate regions of the kidneywhich produce hormones, such as renin, which can be detrimental to apatient in excess. The implants or constrictions can be placed in theaorta 3210 or the renal vein 3230. The implants can be active implants,generating stimulating energy chronically or multiple ablative orinhibitory doses discretely over time.

In the renal vein 3230, the implants 3220, 3200 might cause an increasein the pressure within the kidney (by allowing blood flow to back upinto the kidney and increase the pressure) which will prevent thedownward spiral of systolic heart failure described above because thekidney will act as if it is experiencing a high pressure head. That is,once the pressure in the kidney is restored or artificially elevated byincreased venous pressure, the relative renal hypotension signaling toretain electrolytes and water will not be present any longer and thekidney will “feel” full and the renal sympathetic stimulation will beturned off. In one embodiment, a stent which creates a stenosis isimplanted using a catheter delivery system. In another embodiment, astricture 3220 is created using heat delivered either externally orinternally. Externally delivered heat is delivered via direct heatingvia a percutaneous procedure (through the skin to the region of thekidney) or transmitted through the skin (e.g. with HIFU focused throughthe skin). In one embodiment, an implant is placed between girota'sfascia and the cortex of the kidney. The implant can stimulate orinhibit nerves surrounding the renal blood vessels, or even releasepharmaceuticals in a drug delivery system.

FIG. 7A depicts at least partial ablation of the renal sympatheticnerves 4400 to the kidney using an imaging system such as an MRI machineor CT scanner 4000. The MRI/CT scan can be linked to a focusedultrasound (HIFU) machine to perform the ablations of the sympatheticnerves 4400 around the region of the renal artery 4500. The MRI/CT scanperforms the imaging 4010 and transmits data (e.g. three dimensionalrepresentations of the regions of interest) to the ultrasound controllerwhich then directs the ultrasound to target the region of interest withlow intensity ultrasound (50-1000 mW/cm2), heat (>1000 mW/cm2),cavitation, or a combination of these modalities and/or includingintroduction of enhancing bioactive agent delivery locally orsystemically (sonodynamic therapy). Optionally, a doppler ultrasound orother 3D/4D ultrasound is performed and the data pushed to the MRIsystem to assist with localization of the pathology; alternatively, theultrasound data are utilized to directly control the direction of theenergy being used to target the physiologic processes and CT/MRI is notobtained. Using this imaging and ablation system from a positionexternal to a patient, many regions of the kidney can be treated such asthe internal calyces 4350, the cortex 4300, the medulla 4320, the hilum4330, and the region 4340 close to the aorta. Optionally, anintravascular catheter can be introduced into the patient to augment theprocedure with intravascular energy, temperature measurement, acousticenergy detection, ionizing radiation detection, etc. For example, thecatheter might be able to deliver radiofrequency energy to the wall ofthe blood vessel, or the catheter might be heated in response to themagnetic field being applied across the patient. For example, a balloonor other catheter tip with a metallic coating will be heated in thepresence of a magnetic field. This heat, typically unwanted in thepresence of an intravascular catheter, can be utilized to inhibit, orablate the nerves leading to the kidney (as an example). The MRI systemalso has the advantage of being able to measure temperature and/orlooking at tissue changes around the blood vessels treated, as describedbelow. Similarly, the intravascular catheter can heat up in response toultrasound in the case where the catheter contains elements

Further parameters which can be measured include temperature via thermalspectroscopy using MRI or ultrasound thermometry/elastography; thermalimaging is a well-known feature of MRI scanners; the data for thermalspectroscopy exists within the MRI scan and can be extrapolated from therecorded data in real time by comparing regions of interest before andafter or during treatment. Temperature data overlaid on the MRI scanenables the operator of the machine to visualize the increase intemperature and therefore the location of the heating to insure that thecorrect region has indeed been ablated and that excessive energy is notapplied to the region. Having temperature data also enables control ofthe ablation field as far as applying the correct temperature forablation to the nerves. For example, the temperature over time can bedetermined and fed back to the operator or in an automated system, tothe energy delivery device itself. Furthermore, other spectroscopicparameters can be determined using the MRI scan such as oxygenation,blood flow, inflammation, or other physiologic and functionalparameters. In one embodiment, an alternating magnetic field is used tostimulate and then over-stimulate or inhibit an autonomic nerve (e.g. toor from the kidney).

Elastography is a technique in which the shear waves of the ultrasoundbeam and reflectance are detected. The tissue characteristics change asthe tissue is heated and the tissue properties change. An approximatetemperature can be assigned to the tissue based on elastography and theprogress of the heating can be monitored.

MRI scanners 4000 generally consist of a magnet and an RF coil. Themagnet might be an electromagnet or a permanent magnet. The coil istypically a copper coil which generates a radiofrequency field.Recently, permanent magnets have been utilized to create MRI scannerswhich are able to be used in almost any setting, for example a privateoffice setting. Office based MRI scanners enable imaging to be performedquickly in the convenience of a physician's office as well as requiringless magnetic force (less than 0.5 Tesla) and as a consequence, lessshielding. The lower tesla magnets also provides for special advantagesas far as diversity of imaging and resolution of certain features.Importantly, the permanent magnet MRI scanners are open scanners and donot encapsulate the patient during the scan.

In one embodiment, a permanent magnet MRI is utilized to obtain an MRIimage of the region of interest 4010. High intensity focused 4100ultrasound is used to target the region of interest 4600 identifiedusing the MRI. In one embodiment, the MRI is utilized to detect bloodflow within one or more blood vessels such as the renal arteries, renalveins, superior mesenteric artery, veins, carotid arteries and veins,aortic arch coronary arteries, veins, to name a subset.

Image 4010 is or can be monitored by a health care professional toensure that the region of interest is being treated and the treatmentcan be stopped if the assumed region is not being treated.Alternatively, an imaging algorithm can be initiated in which the regionof interest is automatically (e.g. through image processing) identifiedand then subsequent images are compared to the initial demarcated regionof interest.

Perhaps, most importantly, with MRI, the region around the renalarteries can be easily imaged as can any other region such as the eye,brain, prostate, breast, liver, colon, spleen, aorta, hip, knee, spine,venous tree, and pancreas. The imaging from the MRI can be utilized toprecisely focus the ultrasound beam to the region of interest around therenal arteries or elsewhere in the body. With MRI, the actual nerves tobe modified or modulated can be directly visualized and targeted withthe energy delivered through the body from the ultrasound transducers.One disadvantage of MRI can be the frame acquisition (difficulty intracking the target) rate as well as the cost of introducing an MRImachine into the treatment paradigm. In these regards, ultrasoundimaging offers a much more practical solution. In some embodiments, theadvantages of ultrasound and MRI are combined into a single system. Insome embodiments, an intravascular catheter is further combined with thetwo imaging modalities to further enhance the treatment. In oneembodiment, the intravascular catheter has a ferromagnetic tip which ismoveable or heatable (or both) by the MRI scanner. The tip can bemanipulated, manually or by the magnetic field (or both) to applypressure to the wall of the blood vessel and subsequently heat the wall.In some embodiments, the tip can perform the above function(s) whilemeasuring the temperature of the region around the blood vessel (thenerve region). In other embodiments, another device may be used tomeasure the temperature.

FIG. 7D depicts a method of treating a region with high intensityfocused ultrasound (HIFU). Imaging with an MRI 4520 or ultrasound 4510(or preferably both) is performed. MRI can be used to directly orindirectly (e.g. using functional MRI or spectroscopy) to visualize thesympathetic nerves. T1 weighted or T2 weighted images can be obtainedusing the MRI scanner. In addition to anatomic imaging, the MRI scannercan also obtain temperature data regarding the effectiveness of theablation zone as well as the degree to which the zone is being heatedand which parts of the zones are being heated. Other spectroscopicparameters can be added as well such as blood flow and even nerveactivity. Edema, inflammation, and necrosis can be detected as well withMRI. Ultrasound 4510 can be used to add blood flow to the images usingDoppler imaging. The spectroscopic data can be augmented by imagingmoieties such as particles, imaging agents, or particles coupled toimaging agents which are injected into the patient intravenously, orlocally, and proximal to the region of the renal arteries; these imagingmoieties may be visualized on MRI, ultrasound, or CT scan. Ultrasoundcan also be utilized to determine information regarding heating. Thereflectance of the ultrasonic waves changes as the temperature of thetissue changes. By comparing the initial images with the subsequentimages after heating, the temperature change which occurred after theinstitution of heating can be determined. Therefore, in one embodiment,information regarding heating at baseline is determined and incorporatedinto the treatment modeling during the ongoing treatment at timesubsequent to t=0.

In one embodiment, the kidneys are detected by a cross-sectional imagingmodality such as MRI, ultrasound, or CT scan. The renal arteries andveins are detected within the MRI image utilizing contrast or notutilizing contrast. Next, the imaging data is placed into a threedimensional coordinate system which is linked to one or more ultrasound(e.g. HIFU) transducers 4540 which focus ultrasound onto the region ofthe renal arteries in the coordinate frame 4530. The linking, orcoupling, of the imaging to the therapeutic transducers is accomplishedby determining the 3 dimensional position of the target by creating ananatomic model. The transducers are placed in a relative threedimensional coordinate frame as well. For example, the transducers canbe placed in the imaging field 4520 during the MRI or CT scan such thatthe cross-sectional pictures include the transducers. Optionally, thetransducers contain motion sensors, such as electromagnetic, optical,inertial, MEMS, and accelerometers, one or more of which allow for thetransducer position to be monitored if for example the body movesrelative to the transducer or the operator moves relative to the body.With the motion sensors, the position of the transducers can bedetermined with movement which might occur during the therapy. Theupdated information can then be fed back to the ultrasound therapydevice so as to readjust the position of the therapy.

In one embodiment, a system is described in which the blood flow in therenal artery is detected by detecting the walls of the artery or renalvein or the blood flow in the renal artery or the renal vein. Thecoordinate reference of the blood vessels is then transmitted to thetherapeutic transducer, for example, ultrasound. The therapeutictransducer is directed to the renal blood vessels using the informationobtained by imaging. A model (FIG. 16M for example) of the vessels(including blood flow, movement, etc.) indicates the blood flow of thevessels and the walls of the vessels where the nerves reside. Energy isthen applied to the model of the vessels to treat the nerves around thevessels.

Alternatively, in another embodiment, ultrasound is utilized and theultrasound image 4510 can be directly correlated to the origin of theimaging transducer. In some embodiments the ultrasound is in twodimensions and in others, the ultrasound is presented in threedimensions. In some embodiments, the ultrasound is presented in acombination of two and three dimensions. For example, a two dimensionaltransducer may be quickly rotated at a specified speed and theintegration of the pictures provides a three dimensional approximation.The therapeutic transducer 4540 in some embodiments is the same as theimaging transducer and therefore the therapeutic transducer is bydefinition coupled in a coordinate reference 4540 once the imagingtransducer coordinates are known. If the therapeutic transducer and theimaging transducer are different devices, then they can be coupled byknowledge of the relative position of the two devices. The region ofinterest (ROI) is highlighted in a software algorithm; for example, therenal arteries, the calyces, the medullary region, the cortex, the renalhila, the celiac ganglia, the aorta, or any of the veins of the venoussystem as well. In another embodiment, the adrenal gland, the vesselstraveling to the adrenal gland, or the autonomic nerves traveling to theadrenal gland are targeted with focused ultrasound and then either themedulla or the cortex of the adrenal gland or the nerves and arteriesleading to the gland are partially or fully ablated with ultrasonicenergy.

The targeting region or focus of the ultrasound is the point of maximalintensity. In some embodiments, targeting focus is placed in the centerof the artery such that the walls on either side receive equivalentamounts of energy or power and can be heated more evenly than if onewall of the blood vessel is targeted. In some embodiments in which ablood vessel is targeted, the blood vessel being an artery and theartery having a closely surrounding vein (e.g. the renal artery/veinpedicle), the center of the focus might be placed at the boundary of thevein and the artery.

Once the transducers are energized 4550 after the region is targeted,the tissue is heated 4560 and a technique such as MRI thermography 4570or ultrasound thermography is utilized to determine the tissuetemperature. During the assessment of temperature, the anatomic datafrom the MRI scan or the Doppler ultrasound is then referenced to ensurethe proper degree of positioning and the degree of energy transductionis again further assessed by the modeling algorithm 4545 to set theparameters for the energy transducers 4550. If there is movement of thetarget, the transducers may have to be turned off and the patientrepositioned. Alternatively, the transducers can be redirected to adifferent position within the coordinate reference frame.

Ablation can also be augmented using agents such as magneticnanoparticles or liposomal nanoparticles which are responsive to aradiofrequency field generated by a magnet. These particles can beselectively heated by the magnetic field. The particles can also beenhanced such that they will target specific organs and tissues usingtargeting moieties such as antibodies, peptides, etc. In addition to thedelivery of heat, the particles can be activated to deliver drugs,bioactive agents, or imaging agents at the region at which action isdesired (e.g. the renal artery). The particles can be introduced via anintravenous route, a subcutaneous route, a direct injection routethrough the blood vessel, or a percutaneous route. As an example,magnetic nanoparticles or microparticles respond to a magnetic field(e.g. by a MRI device) by generating heat in a local region around them.Similarly, liposomal particles might have a metallic particle withinsuch that the magnetic particle heats up the region around the liposomebut the liposome allows accurate targeting and biocompatibility.

The addition of Doppler ultrasound 4510 may be provided as well. Therenal arteries are (if renal arteries or regions surrounding thearteries are the target) placed in a 3D coordinate reference frame 4530using a software algorithm with or without the help of fiducial markers.Data is supplied to ultrasound transducers 4540 from a heat modelingalgorithm 4545 and the transducers are energized with the appropriatephase and power to heat the region of the renal artery to between 40° C.and 90° C. within a time span of several minutes. The position withinthe 3D coordinate reference is also integrated into the treatmentalgorithm so that the ultrasound transducers can be moved into theappropriate position. The ultrasound transducers may have frequenciesbelow 1 megahertz (MHz), from 1-20 MHz, or above 30 Mhz, or around 750kHz, 500 kHz, or 250 kHz. The transducers may be in the form of a phasedarray, either annular, linear or curved, or the transducers may bemechanically moved so as to focus ultrasound to the target of interest.In addition, MRI thermography 4570 can be utilized so as to obtain theactual temperature of the tissue being heated. These data can be furtherfed into the system to slow down or speed up the process of ablation4560 via the transducers 4550. For example, in the case where thetemperature is not rising as fast as planned, the energy level can beincreased. On the other hand, where the temperature is rising fasterthan originally planned, the energy density can be decreased.

Aside from focused ultrasound, ultrasonic waves can be utilized directlyto either heat an area or to activate pharmaceuticals in the region ofinterest. There are several methodologies to enhance drug delivery usingfocused ultrasound. For example, particles can release pharmaceuticalswhen they are heated by the magnetic field. Liposomes can release apayload when they are activated with focused ultrasound. Ultrasoundwaves have a natural focusing ability if a transducer is placed in thevicinity of the target and the target contains an activateable moietysuch as a bioactive drug or material (e.g. a nanoparticle sensitive toacoustic waves). Examples of sonodynamically activated moieties includesome porphyrin derivatives.

So as to test the region of interest and the potential physiologiceffect of ablation in that region, the region can be partially heated orvibrated with the focused ultrasound to stun or partially ablate thenerves. Next, a physiologic test such as the testing of blood pressureor measuring norepinephrine levels in the blood, kidney, blood vesselsleading to or from the kidney, can be performed to ensure that thecorrect region was indeed targeted for ablation. Depending on theparameter, additional treatments may be performed.

Clinically, this technique might be called fractionation of therapywhich underscores one of the major advantages of the technique to applyexternal energy versus applying internal energy to the renal arteries.An internal technique requires invasion through the skin and entry intothe renal artery lumens which is costly and potentially damaging.Patients will likely not accept multiple treatments, as they are highlyinvasive and painful. An external technique allows for a less invasivetreatment to be applied on multiple occasions, made feasible by the lowcost and minimal invasion of the technology described herein.

In another embodiment, a fiducial is utilized to demarcate the region ofinterest. A fiducial can be intrinsic (e.g. part of the anatomy) or thefiducial can be extrinsic (e.g. placed in position). For example, thefiducial can be an implanted fiducial, an intrinsic fiducial, or deviceplaced in the blood vessels, or a device placed percutaneously through acatheterization or other procedure. The fiducial can also be a bone,such as a rib, or another internal organ, for example, the liver. In oneembodiment, the fiducial is a beacon or balloon or balloon with a beaconwhich is detectable via ultrasound. In another embodiment, the fiducialis a stent implanted in the renal artery, renal vein, vena cava, oraorta. The stent can be periodically heated by the MRI or ultrasound inthe case where treatment is needed to be reapplied. In one embodiment,the blood flow in the renal arteries, detected via Doppler or B-modeimaging, is the fiducial and its relative direction is determined viaDoppler analysis. Next, the renal arteries, and specifically, the regionaround the renal arteries are placed into a three dimensional coordinateframe utilizing the internal fiducials. A variant of global positioningsystem technology can be utilized to track the fiducials within theartery or around the arteries. In this embodiment, a position sensor isplaced in the artery or vein through a puncture in the groin. Theposition of the sensor is monitored as the sensor is placed into theblood vessel and its position in physical space relative to the outsideof the patient, relative to the operator and relative to the therapeutictransducer is therefore known. The three dimensional coordinate frame istransmitted to the therapeutic ultrasound transducers and then thetransducers and anatomy are coupled to the same coordinate frame. Atthis point, the HIFU is delivered from the transducers, calculating theposition of the transducers based on the position of the target in thereference frame. The fiducial may be active, in which electrical currentis transmitted into the fiducial through a catheter or through inductionof energy transmitted through the skin. The energy transmitted from thecatheter back through the skin or down the catheter and out of thepatient may be utilized to indicate the coordinates of treatmenttarget(s) so that the externally directed energy may be applied at thecorrect location(s). The internal fiducials may be utilized to trackmotion of the region to which energy is being delivered. In someembodiments, there are multiple fiducials within the vessels beingtreated. For example, several fiducials are placed inside the renalartery so that the direction and/or shape of the vessel can bedetermined. Such information is important in the case of tortuosity ofthe blood vessel. Such redundancy can also be used to decrease the errorand increase the accuracy of the targeting and tracking algorithms.

In one embodiment, a virtual fiducial is created via an imaging system.For example, in the case of a blood vessel such as the renal artery, animage of the blood vessel using B-mode ultrasound can be obtained whichcorrelates to the blood vessel being viewed in direct cross section(1705; FIG. 17F). When the vessel is viewed in this type of view, thecenter of the vessel can be aligned with the center 1700 of anultrasound array (e.g. HIFU array 1600) and the transducers can befocused and applied to the vessel, applying heat lesions 1680 to regionsaround the vessel 1705. With different positions of the transducers 1610along a circumference or hemisphere 1650, varying focal points can becreated 1620, 1630, 1640. The directionality of the transducers allowsfor a lesion(s) 1620, 1630, 1640 which run lengthwise along the vessel1700. Thus, a longitudinal lesion 1620-1640 can be produced along theartery to insure maximal inhibition of nerve function. In someembodiments, the center of the therapeutic ultrasound transducer is offcenter relative to the center of the vessel so that the energy isapplied across the vessel wall at an angle, oblique to the vessel. Thetransducer 1600 can also be aspheric in which the focus of thetransducer is off center with respect to its central axis.

In this method of treatment, an artery such as a renal artery is viewedin cross-section or close to a cross-section under ultrasound guidance.In this position, the blood vessel is substantially parallel to the axisof the spherical transducer so as to facilitate lesion production. Thesetup of the ultrasound transducers 1600 has previously been calibratedto create multiple focal lesions 1620, 1630, 1640 along the artery ifthe artery is in cross-section 1680.

In one embodiment, the fiducial is an intravascular fiducial such as aballoon or a hermetically sealed transmitting device. The balloon isdetectable via radiotransmitter within the balloon which is detectableby the external therapeutic transducers. The balloon can have threetransducers, each capable of relaying its position so that the ballooncan be placed in a three dimensional coordinate reference. Once theballoon is placed into the same coordinate frame as the externaltransducers using the transmitting beacon, the energy transducingdevices can deliver energy (e.g. focused ultrasound) to the blood vessel(e.g. the renal arteries) or the region surrounding the blood vessels(e.g. the renal nerves). The balloon and transmitters also enable theability to definitively track the vasculature in the case of movement(e.g. the renal arteries). In another embodiment, the balloon measurestemperature or is a conduit for coolant applied during the heating ofthe artery or nerves. Multiple transducers might be set up outside thepatient to detect the position of the internal fiducial from differentdirections (rather than three internal transducers, in this embodiment,there are three external transducers detecting the position of a singleor multiple internal fiducials). Again, such redundancy in targetingposition is beneficial because the exact position of the internalfiducial may be determined correctly. In another embodiment, multipleinternal fiducials are placed inside the patient, in particular, withina blood vessel to determine the three dimensional orientation of theblood vessel.

Delivery of therapeutic ultrasound energy to the tissue inside the bodyis accomplished via the ultrasound transducers which are directed todeliver the energy to the target in the coordinate frame.

Once the target is placed in the coordinate frame and the energydelivery is begun, it is important to maintain targeting of theposition, particularly when the target is a small region such as thesympathetic nerves. To this end, the position of the region of ablationis compared to its baseline position, both in a three dimensionalcoordinate reference frame. The ongoing positional monitoring andinformation is fed into an algorithm which determines the new targetingdirection of the energy waves toward the target. In one embodiment, ifthe position is too far from the original position (e.g. the patientmoves), then the energy delivery is stopped and the patientrepositioned. If the position is not too far from the original position,then the energy transducers can be repositioned either mechanically(e.g. through physical movement) or electrically via phased array (e.g.by changing the relative phase of the waves emanating from thetransducers). In another embodiment, multiple transducers are placed onthe patient in different positions and each is turned on or off toresult in the necessary energy delivery. With a multitude of transducersplaced on the patient, a greater territory can be covered with thetherapeutic ultrasound. The therapeutic positions can also serve asimaging positions for intrinsic and/or extrinsic fiducials.

In addition to heat delivery, ultrasound can be utilized to delivercavitating energy which may enable drug delivery at certain frequencies.Cavitating energy can also lead to ablation of tissue at the area of thefocus. A systemic dose of a drug can be delivered to the region ofinterest and the region targeted with the cavitating or other forms ofultrasonic energy. Other types of therapeutic delivery modalitiesinclude ultrasound sensitive bubbles or radiation sensitivenanoparticles, all of which enhance the effect of the energy at thetarget of interest. Therefore in one method, an ultrasonically sensitivebioactive material is administered to a patient, and focused ultrasoundis applied through the skin of the patient to the region of the bloodvessels leading to the kidney. The effect of the ultrasound on theregion around the blood vessels is to release the bioactive material orotherwise heat the region surrounding the blood vessel. Theultrasonically sensitive bioactive material may be placed in a vessel,in which cases, ultrasound can be applied through the wall of the bloodvessel to activate the material.

FIG. 7E depicts the anatomy of the region 4600, the kidneys 4620, renalarteries 4630, and bony structures 4610, 4640 as viewed from behind ahuman patient. FIG. 7E depicts the real world placement of the renalarteries into coordinate frame as outlined in FIG. 7D. Cross sectionalCT scans from actual human patients were integrated to create athree-dimensional representation of the renal artery, kidney, andmid-torso region. Plane 4623 is a plane parallel to the transverseprocesses and angle 4607 is the angle one has to look up (toward thehead of the patient) in order to “see” the renal artery under the rib.Such real world imaging and modeling allows for an optimal system to bedeveloped so as to maximize efficacy and minimize risk of the treatment.Therefore with these parameters to consider, a system to treat thenerves surrounding the renal arteries is devised in which a transduceris positionable (e.g., to adjust a line of sight) with a negative anglewith respect to a line connecting the spinal processes. Multipletransducers may be utilized to allow variations in the positioningassociated with variations in anatomy or during respiratory motion,wherein the anatomy may be tracked during treatment.

FIG. 7F depicts an image of the region of the renal arteries and kidney4605 using ultrasound. The renal hilum containing the arteries and veincan be visualized using this imaging modality. This image is typicalwhen looking at the kidney and renal artery from the direction and angledepicted in FIG. 7E. Importantly, at the angle 4607 in 7E, there is norib in the ultrasound path and there no other important structures inthe path either.

An ultrasound imaging trial was then performed to detect the availablewindows to deliver therapeutic ultrasound to the region of the renalarteries 4630 from the posterior region of the patient. It wasdiscovered that the window depicted by arrow 4600 and depicted by arrow4605 in the cross-sectional ultrasound image from ultrasound (FIG. 7F)provided optimal windows to visualize the anatomy of interest (renalpedicle).

FIG. 7G contains some of the important data from the trial 4700, thedata in the “standard position 4730.” These data 4720 can be used todetermine the configuration of the clinical HIFU system to deliverultrasound to the renal hilum. The renal artery 4635 was determined tobe 7-17 cm from the skin in the patients on average. The flank toposterior approach was noted to be optimum to image the renal artery,typically through the parenchyma of the kidney as shown in FIG. 7F 4605.The hilum 4640 of the kidney is approximately 4-8 cm from the ultrasoundtransducer and the angle of approach 4637 (4607 in FIG. 7E) relative toan axis defined by the line connecting the two spinous processes andperpendicular to the spine . . . is approximately −10 to −48 degrees. Itwas also noted that the flank approach through the kidney was the safestapproach in that it represents the smallest chances of applyingultrasound to other organs such as bowel.

Therefore, with these data, a system algorithm for treatment may beendevised: b-mode ultrasound is utilized to visualize the kidney incross-section; doppler ultrasound is utilized to identify the pedicle4640 traveling to the kidney with the renal artery as the identifyinganatomical structure via Doppler ultrasound; the distance to the pedicalis determined via the b-mode imaging. With the kidney inside the b-modeimage, safety can be attained as the kidney has been determined to be anexcellent heat sink and absorber (that is HIFU has little effect on thekidney) of HIFU (see in-vivo data below); the distance is fed into theprocessing algorithm and the HIFU transducer is fed the position data ofthe HIFU transducer. Furthermore, small piezoelectric crystals may belocated at (e.g., along) the therapeutic ultrasound transducer, and maybe utilized to determine a safe path between a source of ultrasound fromthe crystal at the ultrasound transducer and the target blood vessel. Anecho may be sent from the crystal to the target and the time for areturn signal may be determined. With the information about the returnsignal (e.g. distance to target, speed of return), the safety of thepath may be determined. If bowel with air inside (for example) were inthe path, the return signal would deviate from an expected signal, andthe transducer can then be repositioned. Similarly, if bone (e.g. rib)is in the path of the ultrasound beam, the expected return signal willsignificantly deviate from the expected return time, thereby indicatingthat the path cannot be utilized.

Upon further experimentation, it was discovered that by positioning thepatient in the prone position (backside up, abdomen down), thestructures under study 4750 . . . that is, the renal arteries 4770 and4780, the kidney hilum were even closer to the skin and the respiratorymotion of the artery and kidney was markedly decreased. FIG. 7H depictsthese results 4750, 4760 showing the renal artery 4770 at 6-10 cm andthe angle of approach 4790 relative to the spine 4607 shallower at −5 to−20 degrees. Similar results were obtained in the case where the patientremained flat and the legs were propped up using a wedge or bump underthem.

Therefore, with these clinical data, in one embodiment, a method oftreatment 4800 (FIG. 7I) of the renal nerves in a patient has beendevised: 1) identify the rib 4810 and iliac crest 4840 of a patient onthe left and right flank of the patient 4810; 2) identify the left orright sided kidney with ultrasound 4820; 3) identify the hilum of thekidney and the extent the renal hilum is visible along surface ofpatient 4820 using an imaging technology; 4) identify the blood vesselsleading to the kidney from one or more angles, extracting the extent ofvisibility 4860 along the surface area of the patient's back; 5)determine the distance to the one or more of the renal artery, renalvein, kidney, and the renal hilum 4850; 6) optionally, position patientin the prone position with a substantive positioning device underneaththe back of the patient or overtop the abdomen of the patient 4830, tooptimize visibility; 7) optionally determine, through modeling, therequired power to obtain a therapeutic dose at the renal hilum andregion around the renal blood vessels; 8) apply therapeutic energy torenal blood vessels; 9) optionally track the region of the blood vesselsto ensure the continued delivery of energy to the region as planned inthe modeling; 10) optionally, turning off delivery of energy in the casethe focus of the energy is outside of the planned region; 11)optionally, adapting the system through movement of the therapeutic andimaging ultrasound transducers so as to orient the ultrasoundapplicators in relation to the vessel target; 12) optionally placing afiducial in one or more blood vessels to further enhance the device'sability to localize and track the vessel; 13) determining an algorithmfor treatment based on one or more of: the distance to the vessel, thethickness of the skin, the thickness of the muscle, and the thickness ofthe kidney through which the ultrasound traverses; 14) applying thetherapeutic ultrasound with pulses in less than 10 s to ramp up andapply at least 100 W/cm² for at least one second; 15) optionally,directing the therapeutic transducer at an angle anywhere from −5 to −25degrees (i.e. pointing upward toward the cephalic region) relative to aline connecting the spinous proceses.

In another embodiment, FIG. 7J, a clinical algorithm 4900 is depicted inwhich a position of a blood vessel is determined 4910. For example, theblood vessel may be adjacent a nerve region of interest (e.g. renalartery and nerve, aorta and sympathetic nerves, cerebral arteries andnerves, carotid artery and nerves). A test dose of energy is applied tothe threshold of patient sensation 4920. In the case of a renal nerve,the sensation threshold might be a renal colic type of sensation. At thepoint of sensation 4920, the dose can be lowered and cooled and then anadditional dose can be applied at a level just below the sensationthreshold. Such a sequence 4900 can be repeated 4940 many times overuntil the desired effect is achieved. Intermittent off time allows forcooling 4930 of the region. In FIG. 7K, a transducer 4950 is depictedwith both diagnostic and therapeutic ability. Wave 4960 is a diagnosticwave which in this example interferes with bone (rib). In someembodiments, the therapeutic wave which would otherwise emanate fromthis region of the transducer is switched off and therapeutic waves arenot generated. On the other side of the transducer, waves 4956 do indeedallow a clear path to the renal blood vessels 4954 and indeed atherapeutic beam is permitted from this region. The diagnostic energymay be ultrasonic energy, radiofrequency energy, X-ray energy, oroptical energy. For example, MRI, ultrasound, CT scan, or acoustic timeof flight technology might be utilized to determine whether or not aclear path to the renal hilum exists.

In summary, in one technique, a diagnostic test energy is deliveredthrough the skin to the region of the renal blood vessels. Next, anassessment of the visibility of the renal hilum in terms of distance andclearance is made and therapeutic transducers are switched on or offbased on clearance to the renal hilum from a path through the skin. Sucha technique might continue throughout treatment or prior to treatment.

Combining the above data, FIG. 7L depicts a generalized system toinhibit nerves which surround a blood vessel 4975. In a first step, animage of the vessel is produced 4964; next a length of the vessel isscanned 4966; following this step, a direction of the vessel isdetermined in three dimensional space and delivery of a heat cloud isperformed circumferentially around the vessel in which the heat cloud isproduced at least 5 mm from the vessel wall in a radial direction andover a length of at least 5 mm. The cloud is a region of diffused heatwithout focal hot spots. The heat diffuses from the region and can begenerated from inside the vessel or outside the vessel. The vesselitself is protected by convection and removal of heat from the vesselvia the natural blood flow or through the addition of an additionalconvective device in or near the vessel.

The heat cloud can be generated by high intensity ultrasound (seemodeling and data below), radiofrequency energy, and/or optical energy.For example, infrared energy can be delivered through the blood vesselwall to heat the region surrounding the blood vessel. The heating effectcan be detected through MRI thermometry, infrared thermometry, laserthermometry, etc. The infrared light may be applied alone or incombination with phototherapeutic agents.

In some embodiments, a heat cloud is not generated but a cloud toinhibit or ablate nerves in the region may be provided. Such cloud maybe gas (e.g. carbon dioxide), liquid (hot water), phototherapeuticagents, and other toxins such as ethanol, phenol, and neurotoxins.

In contrast to devices which deliver highly focused heat to the wall andrely on conduction or current fall from the vessel wall, a heatcloud orgeneralized cloud presents a potentially safer option in which the nerveablating components are diffused around the vessel.

FIG. 7M depicts an example of delivering a heat cloud 4974 to a bloodvessel from outside the patient 4972. The vessel is placed in a threedimensional coordinate reference. The vessel is targeted duringtreatment. The cloud surrounds the vessels and the entire hilum leadingto the kidney.

FIG. 7N shows a depiction of the nerves leading to the kidney. Thispicture is from an actual dissection of the vessels from a humancadaver. As can be seen, the nerves 4982 surround the blood vesselsleading to the kidney 4984. The heat cloud 4980 is shown surrounding thenerves 4982 leading to the kidney 4984. Importantly, limitation ofprevious catheter based approaches was that the heat cloud could not begenerated around the vessels from a location inside the vessels. Thisheat cloud effectively allows for the target region to be overscannedduring the treatment.

FIG. 7O depicts a cross section of the cloud 4984 surrounding the nerves4986 and vessels 4988. It can be seen that a focal method to heat thenerves through the vessel wall might be difficult to affect a largeportion of the nerves because the nerves are so diffusely presented inthe region in some cases. Therefore, in this embodiment, heat is applieddiffusely to the region surrounding the blood vessel in the form of acloud.

FIG. 8A depicts a percutaneous procedure and device 5010 in which theregion around the renal artery is directly approached through the skinfrom an external position. A combination of imaging and application ofenergy (e.g. ablation) may be performed to ablate the region around therenal artery to treat hypertension, end stage renal disease, diabetes,sleep apnea, and/or heart failure. Probe 5010 is positioned through theskin and in proximity to the kidney 5030. The probe may include sensorsat its tip 5020 which detect heat or temperature or may enableaugmentation of the therapeutic energy delivery. One or more imagingdevices (e.g., CT device, ultrasound device, MRI device) may be utilizedto ensure a clear path for the probe to reach the region of the renalhilum. Ablative, ionizing energy, heat, or light may be applied to theregion to inhibit the sympathetic nerves around the renal artery usingthe probe 5010. Ultrasound, radiofrequency, microwave, direct heatingelements, and balloons with heat or energy sources may be applied to theregion of the sympathetic nerves. Imaging may be included on the probeor performed separately while the probe is being applied to the regionof the renal blood vessels.

In one embodiment, the percutaneous procedure in FIG. 8A is performedunder MRI, CT, or ultrasound guidance to obtain localization orinformation about the degree of heat being applied. In one embodiment,ultrasound is applied but at a sub-ablative dose. That is, the energylevel is enough to damage or inhibit the nerves but the temperature issuch that the nerves are not ablated but paralyzed or partiallyinhibited by the energy. A particularly preferred embodiment would be toperform the procedure under guidance from an MRI scanner because theregion being heated can be determined anatomically in real time as wellvia temperature maps. As described above, the images after heating canbe compared to those at baseline and the signals are compared at thedifferent temperatures.

In one embodiment, selective regions of the kidney are ablated throughthe percutaneous access route; for example, regions which secretehormones which are detrimental to a patient or to the kidneys or otherorgans. Using energy applied externally to the patient through the skinand from different angles affords the ability to target any region in oron the kidney or along the renal nerves or at the region of the adrenalgland, aorta, or sympathetic chain. This greater breadth in the numberof regions to be targeted is enabled by the combination of externalimaging and external delivery of the energy from a multitude of anglesthrough the skin of the patient and to the target. The renal nerves canbe targeted at their takeoff from the aorta onto the renal artery, attheir synapses at the celiac ganglia, or at their bifurcation pointalong the renal artery.

In a further embodiment, probe 5010 can be utilized to detecttemperature or motion of the region while the ultrasound transducers areapplying the energy to the region. A motion sensor, position beacon, oraccelerometer can be used to provide feedback for the HIFU transducers.In addition, an optional temperature or imaging modality may be placedon the probe 5010. The probe 5010 can also be used to locate theposition within the laparoscopic field for the ablations to beperformed. The dose delivered by this probe is approximately

In FIG. 8B, intravascular devices 5050, 5055 are depicted which applyenergy to the region around the renal arteries 5065 from within therenal arteries. The intravascular devices can be utilized to applyradiofrequency, ionizing radiation, and/or ultrasound (either focused orunfocused) energy to the renal artery and surrounding regions. MRI orultrasound or direct thermometry can be further utilized to detect theregion where the heat is being applied while the intravascular catheteris in place.

In one embodiment, devices 5050, 5055 (FIG. 8B) apply ultrasound energywhich inhibits nerve function not by heating, but by mechanisms such asperiodic pressure changes, radiation pressure, streaming or flow inviscous media, and pressures associated with cavitation, defined as theformation of holes in liquid media. Heat can selectively be added tothese energies but not to create a temperature which ablates the nerves,thereby facilitating the mechanism of vibration and pressure. In thisembodiment, the ultrasound is not focused but radiates outward from thesource to essentially create a cylinder of ultrasonic waves thatintersect with the wall of the blood vessel. An interfacial materialbetween the ultrasound transducer and the wall of the artery may beprovided such that the ultrasound is efficiently transduced through thearterial wall to the region of the nerves around the artery. In anotherembodiment, the ultrasound directly enters the blood and propagatesthrough the ultrasound wall to affect the nerves. In some embodiments,cooling is provided around the ultrasound catheter which protects theinside of the vessel yet allows the ultrasound to penetrate through thewall to the regions outside the artery. A stabilization method for theultrasound probe is also included in such a procedure. The stabilizationmethod might include a stabilizing component added to the probe and mayinclude a range finding element component of the ultrasound so that theoperator knows where the ultrasound energy is being applied from outsidethe wall of the blood vessel.

In another embodiment, an ultrasound probe is applied directly to thewall of the blood vessel, utilizing heat and/or vibration to inhibit thenerves surrounding the blood vessel. In this embodiment, the temperatureat the wall of the blood vessel can be measured directly at the cathetertip through laser thermometry or a thermistor. Alternatively, MRI orinfrared thermometry can be used as well.

Imaging can be performed externally or internally in this embodiment inwhich a catheter is placed inside the renal arteries. For example,external imaging with MRI or Ultrasound may be utilized to visualizechanges during the ultrasound modulation of the nerve bundles. Indeed,these imaging modalities may be utilized for the application of any typeof energy within the wall of the artery. For example, radiofrequencydelivery of energy through the wall of the renal artery may be monitoredthrough similar techniques. Thus the monitoring of the proceduralsuccess of the technique is independent of the technique in most cases.In one method, a radiofrequency catheter is applied to the wall of theblood vessel and the temperature of the region around the blood vesselis measured. In another embodiment, heated water vapor is applied to theregion of the blood vessel. In another embodiment, MRI induced heatingof a metallic tipped catheter is detected using MRI thermometry. Inanother embodiment, focused ultrasound is detected using MRIthermometry.

Alternatively, in another embodiment, the devices 5050, 5055 can beutilized to direct externally applied energy (e.g. ultrasound) to thecorrect place around the artery as the HIFU transducers deliver theenergy to the region. For example, the intravascular probe 5050 can beutilized as a homing beacon for the imaging/therapeutic technologyutilized for the externally delivered HIFU.

FIG. 8C depicts a percutaneous procedure to inhibit the renalsympathetic nerves. Probe 5010 is utilized to approach the renal hilum5060 region from posterior and renal artery 5065. With the datapresented below, the probe can be armed with HIFU to denervate theregion. The data presented below indicates the feasibility of thisapproach as far as ultrasound enabling denervation of the vesselsquickly and easily. In another embodiment, a cloud of heat energy isproduced near or around the blood vessel, for example, with warmed gas,with a neurotoxin, with a gas such as carbon dioxide which is known toanesthetize nerves at high concentrations, etc.

In FIG. 8D, a technique is shown in which ultrasound transmitted throughthe wall of a blood vessel 5560 from a catheter 5140 with apiezoelectric crystal 5120 at one end. A detector 5160 is placed outsidethe skin 5112 of the patient to detect the signal emitted from thepiezoelectric. A number of parameters 5170 can be determined/detectedwith this method including position, temperature, acoustic power,radiation pressure, and cavitation threshold. The detection might bedone inside the catheter in some embodiments or at the skin in otherembodiments. In one embodiment, for example, the acoustic impedance fromthe blood vessel to the skin is determined through the detection of thetime of flight of the ultrasound waves from the piezoelectric transduceron the end of the catheter. In another embodiment, structures whichmight block ultrasound are detected by sending a signal to the externaldetector form the internal detector.

FIGS. 8E and 8F depict cross sectional 5200 imaging of the abdomen.Energy waves 5230 are depicted traveling from a posterior directionthrough the skin to the region of the blood vessels 5210 leading to thekidney. Device 5240 can be placed outside the patient on the skin of thepatient, which transmit the waves 5230 to a nerve region surrounding ablood vessel. CT or MRI imaging can be utilized during the procedure tohelp direct the waves. In addition, or alternatively, thermal imaging(e.g. with infrared or laser light) may be used.

In another embodiment, the physiologic process of arterial expansion(aneurysms) is targeted. In FIG. 9 a, an ultrasound transducer is 6005is placed near the wall of an aneurysm 6030. Ultrasonic energy 6015 isapplied to the wall 6030 of the aneurysm to thicken the wall and preventfurther expansion of the aneurysm. In some embodiments, clot within theaneurysm is targeted as well so that the clot is broken up or dissolvedwith the ultrasonic energy. Once the wall of the aneurysm is heated withultrasonic energy to a temperature of between 40 and 70 degrees, thecollagen, elastin, and other extracellular matrix in the wall willharden as it cools, thereby preventing the wall from further expansion.

In another embodiment, a material is placed in the aneurysm sac and thefocused or non-focused ultrasound utilized to harden or otherwise inducethe material in the sac to stick to the aorta or clot in the aneurysmand thus close the aneurysm permanently. In one embodiment therefore, anultrasound catheter is placed in an aorta at the region of an aneurysmwall or close to a material in an aneurysmal wall. The material can be aman-made material placed by an operator or it can be material such asthrombus which is in the aneurysm naturally. Ultrasound is applied tothe wall, or the material, resulting in hardening of the wall or of thematerial, strengthening the aneurysm wall and preventing expansion. Theenergy can also be applied from a position external to the patient orthrough a percutaneously positioned energy delivering catheter.

FIG. 9 b 6000 depicts a clot prevention device 6012 (vena cava filter)within a blood vessel such as the aorta or vena cava 6010. Theultrasound catheter 6005 is applied to the clot prevention device(filter) 6012 so as to remove the clot from the device or to free thedevice 6012 from the wall of the blood vessel in order to remove it fromthe blood vessel 6000.

FIG. 9C depicts a device and method in which the celiac plexus 6020close to the aorta 6000 is ablated or partially heated using heat orvibrational energy from an ultrasonic energy source 6005 which can applyfocused or unfocused sound waves 6007 at frequencies ranging from 20kilohertz to 5 Mhz and at powers ranging from 1 mW to over 100 kW in afocused or unfocused manner. Full, or partial ablation of the celiacplexus 6020 can result in a decrease in blood pressure via a similarmechanism as applying ultrasonic energy to the renal nerves; theablation catheter is a focused ultrasound catheter but can also be adirect (unfocused) ultrasonic, a microwave transducer, or a resistiveheating element. Energy can also be delivered from an external positionthrough the skin to the aorta or celiac plexus region.

FIG. 10 depicts a method 6100 to treat a patient with high intensity orlow intensity focused ultrasound (HIFU or LIFU) 6260. In a first step, aCT and/or MRI scan and/or thermography and/or ultrasound (1D,2D,3D) isperformed 6110. A fiducial or other marking on or in the patient 6120 isoptionally used to mark and track 6140 the patient. The fiducial can bean implanted fiducial, a temporary fiducial placed internally orexternally in or on the patient, or a fiducial intrinsic to the patient(e.g. bone, blood vessel, arterial wall) which can be imaged using theCT/MRI/Ultrasound devices 6110. The fiducial can further be a temporaryfiducial such as a catheter temporarily placed in an artery or vein of apatient or a percutaneously placed catheter. A planning step 6130 forthe HIFU treatment is performed in which baseline readings such asposition of the organ and temperature are determined; a HIFU treatmentis then planned using a model (e.g. finite element model) to predictheat transfer, or pressure to heat transfer, from the ultrasoundtransducers 6130. The planning step incorporates the information on thelocation of the tissue or target from the imaging devices 6110 andallows placement of the anatomy into a three dimensional coordinatereference such that modeling 6130 can be performed.

The planning step 6130 includes determination of the positioning of theultrasound transducers as far as position of the focus in the patient.X,Y,Z, and up to three angular coordinates are used to determine theposition of the ultrasonic focus in the patient based on the crosssectional imaging 6110. The HIFU transducers might have their ownposition sensors built in so that the position relative to the targetcan be assessed. Alternatively, the HIFU transducers can be rigidlyfixed to the table on which the patient rests so that the coordinatesrelative to the table and the patient are easily obtainable. The flow ofheat is also modeled in the planning step 6130 so that the temperatureat a specific position with the ultrasound can be planned and predicted.For example, the pressure wave from the transducer is modeled as itpenetrates through the tissue to the target. For the most part, thetissue can be treated as water with a minimal loss due to interfaces.Modeling data predicts that this is the case. The relative power andphase of the ultrasonic wave at the target can be determined by thepositional coupling between the probe and target. A convective heattransfer term is added to model heat transfer due to blood flow,particularly in the region of an artery. A conductive heat transfer termis also modeled in the equation for heat flow and temperature.

Another variable which is considered in the planning step is the size ofthe lesion and the error in its position. In the ablation of smallregions such as nerves surrounding blood vessels, the temperature of theregions may need to be increased to a temperature of 60-90 degreesCelsius to permanently ablate nerves in the region. Temperatures of40-60 degrees may temporarily inhibit or block the nerves in theseregions and these temperatures can be used to determine that a patientwill respond to a specific treatment without permanently ablating thenerve region. Subsequently, additional therapy can be applied at a latertime so as to complete the job or perhaps, re-inhibit the nerve regions.In some embodiments, the temperature inside the blood vessel is measuredand held to a temperature of less than 60 degrees Celsius, or less than70 degrees Celsius, in which case the procedure might be stopped (e.g.,when a desired temperature is reached).

An error analysis is also performed during the treatment contemplated inFIG. 10. Each element of temperature and position contains an errorvariable which propagates through the equation of the treatment. Theerrors are modeled to obtain a virtual representation of the temperaturemapped to position. This map is correlated to the position of theultrasound transducers in the treatment of the region of interest.

During the delivery of the treatment 6260, the patient may move, inwhich case the fiducials 6120 track the movement and the position of thetreatment zone is re-analyzed 6150 and the treatment is restarted or thetransducers are moved either mechanically or electrically to a new focusposition.

In another embodiment, a cross-sectional technique of imaging is used incombination with a modality such as ultrasound to create a fusion typeof image. The cross-sectional imaging is utilized to create a threedimensional data set of the anatomy. The ultrasound, providing twodimensional images, is linked to the three dimensional imaging providedby the cross-sectional machine through fiducial matches between theultrasound and the MRI. As a body portion moves within the ultrasoundfield, the corresponding data is determined (coupled to) thecross-sectional (e.g. MRI image) and a viewing station can show themovement in the three dimensional dataset. The ultrasound provides realtime images and the coupling to the MRI or other cross-sectional imagedepicts the ultrasound determined position in the three dimensionalspace.

FIG. 11 depicts the treatment 7410 of another disease in the body of apatient, this time in the head of a patient. Subdural and epiduralhematomas occur as a result of bleeding of blood vessels in the dural orepidural spaces of the brain, spinal column, and scalp. FIG. 11 depictsa CT or MRI scanner 7300 and a patient 7400 therein. An image isobtained of the brain 7000 using a CT or MRI scan. The image is utilizedto couple the treatment zone 7100 to the ultrasound array utilized toheat the region. In one embodiment 7100, a subdural hematoma, eitheracute or chronic, is treated. In another embodiment 7200, an epiduralhematoma is treated. In both embodiments, the region of leakingcapillaries and blood vessels are heated to stop the bleeding, or in thecase of a chronic subdural hematoma, the oozing of the inflammatorycapillaries.

In an exemplary embodiment of modulating physiologic processes, apatient 7400 with a subdural or epidural hematoma is chosen fortreatment and a CT scan or MRI 7300 is obtained of the treatment region.Treatment planning ensues and the chronic region of the epidural 7200 orsub-dural 7010 hematoma is targeted for treatment with the focusedultrasound 7100 transducer technology. Next the target of interest isplaced in a coordinate reference frame as are the ultrasoundtransducers. Therapy 7100 ensues once the two are coupled together. Thefocused ultrasound heats the region of the hematoma to dissolve the clotand/or stop the leakage from the capillaries which lead to theaccumulation of fluid around the brain 7420. The technology can be usedin place of or in addition to a burr hole, which is a hole placedthrough the scalp to evacuate the fluid.

FIG. 12 depicts a laparoscopic based approach 8000 to the renal arteryregion in which the sympathetic nerves 8210 can be ligated, interrupted,or otherwise modulated. In laparoscopy, the abdomen of a patient isinsufflated and laparoscopic instruments introduced into the insufflatedabdomen. The retroperitoneum is easily accessible through a flankapproach or (less so) through a transabdominal (peritoneal) approach. Alaparoscopic instrument 8200 with a distal tip 8220 can apply heat oranother form of energy or deliver a drug to the region of thesympathetic nerves 8210. The laparoscopic instrument can also beutilized to ablate or alter the region of the celiac plexus 8300 andsurrounding ganglia. The laparoscope can have an ultrasound transducer8220 attached, a temperature probe attached, a microwave transducerattached, or a radiofrequency transducer attached. The laparoscope canbe utilized to directly ablate or stun the nerves (e.g. with a lowerfrequency/energy) surrounding vessels or can be used to ablate or stunnerve ganglia which travel with the blood vessels. Similar types ofmodeling and imaging can be utilized with the percutaneous approach aswith the external approach to the renal nerves. With the discoverythrough animal experimentation (see below) that a wide area of nerveinhibition can be affected with a single ultrasound probe in a singledirection (see above), the nerve region does not have to be directlycontacted with the probe, the probe instead can be directed in thegeneral direction of the nerve regions and the ultrasound delivered. Forexample, the probe can be placed on one side of the vessel and activatedto deliver focused or semi-focused ultrasound over a generalized regionwhich might not contain greater than 1 cm of longitudinal length of theartery but its effect is enough to completely inhibit nerve functionalong.

FIG. 13 depicts an algorithm 8400 for the treatment of a region ofinterest using directed energy from a distance. MRI and/or CT with orwithout an imaging agent 8410 can be utilized to demarcate the region ofinterest (for example, the ablation zone) and then ablation 8420 can beperformed around the zone identified by the agent using any of themodalities above. This algorithm is applicable to any of the therapeuticmodalities described above including external HIFU, laparoscopicinstruments, intravascular catheters, percutaneous catheters andinstruments, as well as any of the treatment regions including the renalnerves, the eye, the kidneys, the aorta, or any of the other nervessurrounding peripheral arteries or veins. Imaging 8430 with CT, MRI,ultrasound, or PET can be utilized in real time to visualize the regionbeing ablated. At such time when destruction of the lesion is complete8440, imaging with an imaging (for example, a molecular imaging agent ora contrast agent such as gadolinium) agent 8410 can be performed again.The extent of ablation can also be monitored by monitoring thetemperature or the appearance of the ablated zone under an imagingmodality. Once lesion destruction is complete 8440, the procedure isfinished. In some embodiments, ultrasonic diagnostic techniques such aselastography are utilized to determine the progress toward heating orablation of a region.

FIG. 14 depicts ablation in which specific nerve fibers of a nerve aretargeted using different temperature gradients, power gradients, ortemperatures 8500. For example, if temperature is determined by MRIthermometry or with another technique such as ultrasound, infraredthermography, or a thermocouple, then the temperature can be kept at atemperature in which only certain nerve fibers are targeted fordestruction or inhibition. Alternatively, part or all of the nerve canbe turned off temporarily to then test the downstream effect of thenerve being turned off. For example, the sympathetic nerves around therenal artery can be turned off with a small amount of heat or otherenergy (e.g. vibrational energy) and then the effect can be determined.For example, norepinephrine levels in the systemic blood, kidney, orrenal vein can be assayed; alternatively, the stimulation effect of thenerves can be tested after temporary cessation of activity (e.g. skinreactivity, blood pressure lability, cardiac activity, pulmonaryactivity, renal artery constriction in response to renal nervestimulation). For example, in one embodiment, the sympathetic activitywithin a peripheral nerve is monitored; sympathetic activity typicallymanifests as spikes within a peripheral nerve electrical recording. Thenumber of spikes correlates with the degree of sympathetic activity orover-activity. When the activity is decreased by (e.g. renal arteryde-inervation), the concentration of spikes in the peripheral nervetrain is decreased, indicating a successful therapy of the sympatheticor autonomic nervous system. Varying frequencies of vibration can beutilized to inhibit specific nerve fibers versus others. For example, insome embodiments, the efferent nerve fibers are inhibited and in otherembodiments, the afferent nerve fibers are inhibited. In someembodiments, both types of nerve fibers are inhibited, temporarily orpermanently. In some embodiments, the C fibers 8520 are selectivelyblocked at lower heat levels than the A nerve fibers. In otherembodiment, the B fibers are selectively treated or blocked and in someembodiments, the A fibers 8530 are preferentially blocked. In someembodiments, all fibers are inhibited by severing the nerve with a highdose of ultrasound 8510. Based on the experimentation described above,the power density to achieve full blockage might be around 100-800 W/cm²or with some nerves from about 500 to 2500 W/cm². In some embodiments, apulse train of 100 or more pulses each lasting 1-2 seconds (for example)and delivering powers from about 50 w/cm² to 500 W/cm². Indeed, priorliterature has shown that energies at or about 100 W/Cm² is adequate todestroy or at least inhibit nerve function (Lele, PP. Effects of FocusedUltrasound Radiation on Peripheral Nerve, with Observations on LocalHeating. Experimental Neurology 8, 47-83 1963). Based on data obtainedin proof of concept, the ramp up to the correct power is desirable insome embodiments due to the nature of the region in which there is atremendous amount of perfusion through the large blood vessels throughthe renal vein, artery, vena cava, etc. Modeling indicates that a slowincrease in power ramp up allows the blood vessels to remove a greateramount of heat than when the rise in temperature is performed within afew seconds.

FIG. 15 a depicts treatment 8600 of a vertebral body or intervertebraldisk 8610 in which nerves within 8640 or around the vertebral column8630 are targeted with energy 8625 waves. In one embodiment, nervesaround the facet joints are targeted. In another embodiment, nervesleading to the disks or vertebral endplates are targeted. In anotherembodiment, nerves within the vertebral bone 8630 are targeted byheating the bone itself. Sensory nerves run through canals 8635 in thevertebral bone 8630 and can be inhibited or ablated by heating the bone8630. In one method of treatment, focused ultrasound is applied from aposition external to a patient and energy directed toward the vertebralbone; the bone is heated by the focused ultrasound and the nerve insidethe bone is injured or paralyzed by the heat inside the bone. Suchmethodology can also be utilized to harden bone in the context oftreating a vertebral body fracture to quell the pain response to thefracture.

FIG. 15B depicts a close-up of the region of the facet joint. Focusedultrasound to this region can inhibit nerves involved in back pain whichoriginate at the dorsal root nerve and travel to the facet joint 8645.Ablation or inhibition of these nerves can limit or even cure back paindue to facet joint arthropathy. Focused ultrasound can be applied to theregion of the facet joint from a position outside the patient to thefacet joint using powers of between 100 W/cm² and 2500 W/cm² at thenerve from times ranging from 1 second to 10 minutes.

FIG. 16A depicts a set of lesion types, sizes, and anatomies 8710 a-fwhich lead to de-innervation of the different portions of thesympathetic nerve tree around the renal artery. For example, the lesionscan be annular, cigar shaped, linear, doughnut and/or spherical; thelesions can be placed around the renal arteries 8705, inside the kidney8710, and/or around the aorta 8700. For example, the renal arterial treecomprises a portion of the aorta 8700, the renal arteries 8705, andkidneys 8715. Lesions 8714 and 8716 are different types of lesions whichare created around the aorta 8700 and vascular tree of the kidneys.Lesions 8712 and 8718 are applied to the pole branches from the renalartery leading to the kidney and inhibit nerve functioning at branchesfrom the main renal artery. These lesions also can be applied from aposition external to the patient. Lesions can be placed in a spiralshape 8707 along the length of the artery as well. These lesions can beproduced using energy delivered from outside the blood vessels using acompletely non-invasive approach in which the ultrasound is appliedthrough the skin to the vessel region or the energy can be delivered viapercutaneous approach. Either delivery method can be accomplishedthrough the posterior approach to the blood vessels as discovered anddescribed above.

In one method therefore, ultrasound energy can be applied to the bloodvessel leading to a kidney in a pattern such that a circular pattern ofheat and ultrasound is applied to the vessel. The energy is transmittedthrough the skin in one embodiment or through the artery in anotherembodiment. As described below, ultrasound is transmitted from adistance and is inherently easier to apply in a circular pattern becauseit doesn't only rely on conduction.

Previously, it was unknown and undiscovered whether or not the annularshaped lesions as shown in FIG. 16 a would have been sufficient to blocknerve function of the autonomic nerves around the blood vessels.Applicant of the subject application discovered that the annular shapedablations 8710 not only block function but indeed completely block nervefunction around the renal artery and kidney and with very minimal damage(FIG. 16C), if any, to the arteries and veins themselves. In theseexperiments, focused ultrasound was used to block the nerves; theultrasound was transmitted through and around the vessel from the top(that is, only one side of the vessel) at levels of 200-2500 W/cm². Theenergy travels through the flowing blood to affect the opposite side ofthe blood vessel. Simulations are shown in FIGS. 16B and 16D anddescribed below. Norepinephrine levels in the kidney 8780, which areutilized to determine the degree of nerve inhibition, were determinedbefore and after application of energy. The lower the levels ofnorepinephrine, the more nerves which have been inhibited or affected.In these experiments which were performed, the norepinephrine levelsapproached zero 8782 versus controls (same animal, opposite kidney) 8784which remained high. In fact, the levels were equal to or lower than thesurgically denuded blood vessels (surgical denudement involves directlycutting the nerves surgically and application of phenol to the vesselwall). It is important to note that the renal artery and vein wallsremained substantially unharmed; this is likely due to the fact that thequick arterial blood flow removes heat from the vessel wall and the factthat the main renal artery is extremely resilient due to its large size,high blood flow, and thick wall; these findings are consistent with themodeling performed as shown in FIGS. 16B and 16D. To summarize,ultrasound (focused and relatively unfocused) was applied to one side ofthe renal artery and vein complex. The marker of nerve inhibition,norepinephrine levels inside the kidney, were determined to beapproaching zero after application to the nerves from a singledirection, transmitting the energy through the artery wall to reachnerves around the circumference of the artery. The level of zeronorepinephrine 8782 indicates essentially complete abolition of nervefunction proving that the annular lesions were in fact created asdepicted in FIG. 16A and simulated in FIGS. 16B and 16D. Histologicalresults also confirm the annular nature of the lesions and limitedcollateral damage as predicted by the modeling in 16B.

Therefore, in one embodiment, the ultrasound is applied from a positionexternal to the artery in such a manner so as to create an annular orsemi-annular rim of heat all the way around the artery to inhibit,ablate, or partially ablate the autonomic nerves surrounding the artery.The walls or the blood flow of the artery can be utilized to target theultrasound to the nerves which, if not directly visualized, arevisualized through use of a model to approximate the position of thenerves based on the position of the blood vessel.

FIG. 16B further supports the physics and physiology described herein,depicting a theoretical simulation 8750 of the physical and animalexperimentation described above. That is, focused ultrasound wastargeted to a blood vessel in a computer simulation 8750. The renalartery 8755 is depicted within the heating zone generated within afocused ultrasound field. Depicted in the figure is the temperature at<1 s 8760 and at approximately 5 s 8765 and longer time >10 s 8767. Flowdirection 8770 is shown as well. The larger ovals depict highertemperatures with the central temperature >100° C. The ultrasound fieldis transmitted through the artery 8755, with heat building up around theartery as shown via the temperature maps 8765. Importantly, thistheoretical simulation also reveals the ability of the ultrasound totravel through the artery or blood vessel 8767 and affect both walls ofthe blood vessel. These data are consistent with the animalexperimentation described above, creating a unified physical andexperimental dataset. In some cases, the ultrasonic energy may beapplied to the blood vessel quickly to avoid removal of the heat by theblood flow. In the case where the ultrasound ramp up around the vesselis not applied quickly, a steady state is reached in which the heatapplied is equal to the heat dissipated, and it may become difficult toheat the rim of the blood vessel.

FIG. 16C depicts the results of an experimental focused ultrasoundtreatment in which one kidney was treated with the ultrasound and theother served as a control. Norepinephrine 8780 is the marker of theeffect of sympathetic nerve inhibition and its concentration wasmeasured in the cortex of the kidney. The experimental result 8782 wasvery low compared to the control 8784 level indicating almost completeinhibition of the nerves which travel to the kidney. A circumferentialeffect of the heat is provided to obtain such a dramatic effect onnorepinephrine levels leading to the kidney.

FIG. 16D is a depiction of a simulation with multiple beams beingapplied to the region of the blood vessel wall. The ultrasound might bescanned toward the blood vessel or otherwise located point by pointwithin the treatment region. In one embodiment, the power to the bloodvessel is delivered such that the temperature ramps over 60 degreeswithin 2 s or within 5 s or within 10 s. Subsequently, the energy isturned off and then reapplied after a period of 1, 2, 5, or 10 seconds.In some embodiments, the energy may be on for a prescribed duration,such as 1, 2, 5, 10 seconds, etc. In some embodiments, a technique suchas infrared thermography or laser Doppler thermography is used todetermine the temperature of the skin and subcutaneous tissue to decidewhen it is safe to deliver an additional dose of energy to the targetzone. Such a treatment plan creates a cloud of heat centered on theinside of the wall of the blood vessel. In other embodiments, the energymay be on for 30, 60, or 90 seconds, but the power is lower than thatfor the shorter on-time periods of 1, 2, 5, 10 seconds.

Similarly, other vessels leading to other organs which rely onsympathetic, parasympathetic, and general autonomic innervation can betreated as well utilizing this technique. Referring to FIG. 5C, bloodvessels which lead to the eye 2105 (carotid artery), the mouth (facialarteries) and saliva glands 2107, the heart 2109, the bronchi 2110, thestomach 2112, the gallbladder 2114 and liver 2118, the bladder 2114, theadrenal gland 2116, the pancreas can be stimulated or inhibitedutilizing this technique of focused energy delivery targeting a bloodvessel. In one example, an underactive pancreas is treated bydenervation, which results in improved glucose tolerance. In anotherembodiment, the liver is denervated by ablated arteries surroundingportal veins or hepatic arteries leading to the liver. Any of the aboveorgans may be denervated using a similar technique as that describedwith reference to the blood vessels leading to the kidney.

FIGS. 16D-H depict another simulation with multiple treatment performedover time (up to 132 s) in a pattern such as shown in FIG. 16D. FIG. 16His a close up of FIG. 16D and depicts a blood vessel 8795 (with a flowrate of the renal artery and renal vein in a human being) and vesselwall 8796. In this simulation, the focused energy was applied in a 10 son and 6 s off pattern to allow heat to surround 8793 the vessel 8795.The transducer 8790, subcutaneous tissue 8792, and muscle wall 8794 aredepicted. This simulation reveals the ability of focused energy tocreate a cloud around the blood vessel particularly with high blood flowsuch as to the kidney.

FIGS. 16 I,J,K depict some of the patterns which can be applied to ablood vessel. In FIG. 16D, application of the focused energy 8770 to thevessel is shown in a pattern created by the transducer mover. FIG. 16Idepicts another type of pattern 8772 with a broader brush stroke aroundthe vessel.

FIG. 16I and FIG. 16J depict cross sectional patterns across a bloodvessel. FIG. 16K depicts a longitudinal pattern 8774 along the vessel.

FIGS. 16L and 16M depict the results of an experiment 8787 in whichnerves leading to the kidney are treated with heat from an externallyapplied source, and nerves inhibited from producing norepinephrine.

FIG. 16L depicts the results of an experiment in which the HIFU 8644 wascompared to a surgical control 8648. HIFU was applied across the vesselso that the ultrasound passed through the blood and the vessel to affectboth walls of the vessel. As can be seen in the FIG. 16L, the HIFUapplied from outside the patient is as good as denervation with surgeryrevealing that focused ultrasound can indeed remove, inhibit, or ablatenerves surrounding blood vessels. To the extent nerves are containedwithin the walls of the blood vessel, focused ultrasound can be used toinhibit or ablate the nerves within the media of the blood vessel wall.

FIG. 16M depicts a similar experiment in which focused ultrasound isapplied through the skin to the nerves surrounding the blood vesselstraveling to the kidney. Bar 8788 is a control kidney and 8778 is atherapy kidney. A pattern of heat is applied to the blood vessel over a2-3 minute period resulting in the observed changes in norepinephrineand indicating denervation of the sympathetic nerves around a bloodvessel leading to an organ.

As can be seen, the control side 8788, 8644, 8646, 8648 reveal a highnorepinephrine level and the therapy side 8778, 8649 reveals a lownorepinephrine level, indicating treatment was successful. Thisexperiment was performed utilizing an externally placed ultrasoundsystem which focused the energy on the nerves in one of the patternsshown above.

Therefore, based on the animal and theoretical experimentation, there isproven feasibility of utilizing ultrasound to quickly and efficientlyinhibit the nerves around the renal arteries from a position external tothe blood vessels as well as from a position external to the skin of thepatient.

The pattern of application may be different from systems to treat tumorsand other pathologies in which it is desired that 100% of the region betreated. The nerve region surrounding the blood vessels is diffuse andit is not necessary to inhibit all nerves in order to have an effect onblood pressure. Therefore, the goal is to apply broad brush strokes ofenergy across the vessel to create an annular zone, or cloud of heataround the vessel. Subsequent to a first treatment, a second treatmentmay be applied in which additional nerves are affected. The secondtreatment may occur minutes, hours, days, or years after the treatment,and may depend on physiological changes or regrowth of the nerves. Insome cases, a quality factor is calculated based on the degree ofmovement of the applicator. The quality factor relates to the degree oftime the applicator actually was focused on the identified target.Although 100% is ideal, sometimes it may not be achieved. Therefore, insome cases, when the applicator focuses on the target for 90% of thetime, the treatment may be considered successful. In other embodiments,the quality factor might be the amount of time the targeted region isactually within 90% of the target, for example, within 500 microns ofthe target, or within 1 mm of the target, or within 2 mm of the target,etc. The detection of the target is determined via imaging, internalfiducial, and/or external fiducial.

Utilizing the experimental simulations and animal experimentationdescribed above, a clinical device can and has been devised and testedin human patients. FIG. 17A depicts a multi-transducer HIFU device 1100which applies a finite lesion 1150 along an artery 1140 (e.g. a renalartery) leading to a kidney 1130. The lesion can be spherical in shape,cigar shaped 1150, annular shaped 8710 (FIG. 16A), or point shaped;however, in a preferred embodiment, the lesion runs along the length ofthe artery and has a cigar shape 1150. This lesion is generated by aspherical or semi-spherical type of ultrasound array in a preferredembodiment. Multiple cigar shaped lesions as shown in FIG. 17C lead to aring type of lesion 1350.

FIG. 17B depicts an imaging apparatus display which monitors treatment.Lesion 1150 is depicted on the imaging apparatus as is the aorta 1160and renal artery 1155. The image might depict heat, tissue elastography,vibrations, temperature or might be based on a simulation of theposition of the lesion 1150. MRI, CT, infrared thermography, ultrasound,laser thermography, or thermistors may be used to determine temperatureof the tissue region. FIG. 17C depicts another view of the treatmentmonitoring, with the renal artery in cross section 1340. Lesion 1350 isdepicted in cross section in this image as well. The lesion 1350 mightbe considered to circumscribe the vessel 1340 in embodiments wheremultiple lesions are applied.

FIG. 17D depicts a methodology 1500 to analyze and follow the deliveryof therapeutic focused ultrasound to an arterial region. A key step isto first position 1510 the patient optimally to image the treatmentregion; the imaging of the patient might involve the use of Dopplerimaging, M mode imaging, A scan imaging, or even MRI, fluoroscopy, or CTscan. The imaging unit is utilized to obtain coordinate data 1530 fromthe doppler shift pattern of the artery. Next, the focused ultrasoundprobe is positioned 1520 relative to the imaged treatment region 1510and treatment can be planned or applied.

FIG. 17E depicts the pathway of the acoustic waves from a spherical orcylindrical type of ultrasound array 1600. In some embodiments, thetransducer is aspherical such that a sharp focus does not exist butrather the focus is more diffuse in nature or off the central axis.Alternatively, the asphericity might allow for different pathlengthsalong the axis of the focusing. For example, one edge of the ultrasoundtransducer might be called upon for 15 cm of propagation while anotheredge of the transducer might be called upon to propagate only 10 cm, inwhich case a combination of different frequencies or angles might berequired.

Ultrasound transducers 1610 are aligned along the edge of a cylinder1650, aimed so that they intersect at one or more focal spots 1620,1630, 1640 around the vessel (e.g. renal artery). The transducers 1610are positioned along the cylinder or sphere or spherical approximation(e.g. aspherical) 1650 such that several of the transducers are closerto one focus or the other such that a range of distances 1620, 1630,1640 to the artery is created. The patient and artery are positionedsuch that their centers 1700 co-localize with the center of theultrasound array 1600. Once the centers are co-localized, the HIFUenergy can be activated to create lesions along the length of the arterywall 1640, 1620, 1630 at different depths and positions around theartery. The natural focusing of the transducers positioned along acylinder as in FIG. 17E is a lengthwise lesion, longer than in thicknessor height, which will run along the length of an artery 1155 when theartery 1340 is placed along the center axis of the cylinder. When viewedalong a cross section (FIG. 17F), the nerve ablations are positionedalong a clock face 1680 around the blood vessel.

In another embodiment, a movement system for the transducers is utilizedso that the transducers move along the rim of the sphere or cylinder towhich they are attached. The transducers can be moved automatically orsemi-automatically, based on imaging or based on external positionmarkers. The transducers are independently controlled electrically butcoupled mechanically through the rigid structure.

Importantly, during treatment, a treatment workstation 1300 (FIG. 17C)gives multiple views of the treatment zone with both physical appearanceand anatomy 1350. Physical modeling is performed in order to predictlesion depth and the time to produce the lesion; this information is fedback to the ultrasound transducers 1100. The position of the lesion isalso constantly monitored in a three dimensional coordinate frame andthe transducer focus at lesions center 1150 in the context of monitoring1300 continually updated.

In some embodiments, motion tracking prevents the lesion or patient frommoving too far out of the treatment zone during the ablation. If thepatient does move outside the treatment zone during the therapy, thenthe therapy can be stopped. Motion tracking can be performed using theultrasound transducers, tracking frames and position or with transducersfrom multiple angles, creating a three dimensional image with thetransducers. Alternatively, a video imaging system can be used to trackpatient movements, as can a series of accelerometers positioned on thepatient which indicate movement. In some cases, this embodiment caninclude a quality factor used to change the dose delivered to thepatient based on movement which tends to smear the delivered dose, asdescribed herein.

FIG. 18 depicts a micro-catheter 8810 which can be placed into renalcalyces 8820; this catheter allows the operator to specifically ablateor stimulate 8830 regions of the kidney 8800. The catheter can be usedto further allow for targeting of the region around the renal arteriesand kidneys by providing additional imaging capability or by assistingin movement tracking or reflection of the ultrasound waves to create orposition the lesion. The catheter or device at or near the end of thecatheter may transmit signals outside the patient to direct an energydelivery device which delivers energy through the skin. Signalingoutside the patient may comprise energies such as radiofrequencytransmission outside the patient or radiofrequency from outside to theinside to target the region surrounding the catheter. The followingpatent and patent applications describe the delivery of ultrasound usinga targeting catheter within a blood vessel, and are expresslyincorporated by reference herein:

Ser. Nos. 11/583,569, 12/762,938, 11/583,656, 12/247,969, 10/633,726,09/721,526, 10/780,405, 09/747,310, 12/202,195, 11/619,996, 09/696,076

In one system 8800, a micro catheter 8810 is delivered to the renalarteries and into the branches of the renal arteries in the kidney 8820.A signal is generated from the catheter into the kidney and out of thepatient to an energy delivery system. Based on the generated signal, theposition of the catheter in a three dimensional coordinate reference isdetermined and the energy source is activated to deliver energy 8830 tothe region indicated by the microcatheter 8810.

In an additional embodiment, station keeping is utilized. Stationkeeping enables the operator to maintain the position of the externalenergy delivery device with respect to the movement of the operator ormovement of the patient. As an example, targeting can be achieved withthe energy delivery system and tracking of movement of the energydelivery system relative to the target. As the energy delivery systemmoves from its initial state, the station keeping allows the focus to bemoved with the target as the target moves from its original position.Such station keeping is described herein and illustrated in FIGS. 19C-D.A quality factor may be used by the device to increase or decreasedosing depending on the degree of movement. For example, if the qualityfactor deviation from a desired value by a certain amount, then the dosemay be increased or decreased.

The microcatheter may be also be utilized to place a flow restrictorinside the kidney (e.g. inside a renal vein) to “trick” the kidney intothinking its internal pressure is higher than it might be. In thisembodiment, the kidney generates signals to the central nervous systemto lower sympathetic output to target organs in an attempt to decreaseits perfusion pressure.

Alternatively, specific regions of the kidney might be responsible forhormone excretion or other factors which lead to hypertension or otherdetrimental effects to the cardiovascular system. The microcatheter cangenerate ultrasound, radiofrequency, microwave, or X-ray energy. Themicrocatheter can be utilized to ablate regions in the renal vein orintra-parenchymal venous portion as well. In some embodiments, ablationis not required but vibratory energy emanating from the probe isutilized to affect, on a permanent or temporary basis, themechanoreceptors or chemoreceptors in the location of the hilum of thekidney.

FIG. 19A depicts the application 8900 of energy to the region of therenal artery 8910 and kidney 8920 using physically separated transducers8930, 8931. Although two are shown, the transducer can be a singletransducer which is connected all along an outer frame. Thetransducer(s) can be spherical (sharp focus) or aspherical (diffusefocus), they can be coupled to an imaging transducer directly orindirectly where the imaging unit might be separated at a distance. Incontrast to the delivery method of FIG. 17, FIG. 19A depicts delivery ofultrasound transverse to the renal arteries and not longitudinal to theartery. The direction of energy delivery is the posterior of the patientbecause the renal artery is the first vessel “seen” when traveling fromthe skin toward the anterior direction facilitating delivery of thetherapy. In one embodiment, the transducers 8930, 8931 are placed under,or inferior to the rib of the patient or between the ribs of a patient;next, the transducers apply an ultrasound wave propagating forwardtoward the anterior abdominal wall and image the region of the renalarteries and renal veins, separating them from one another. In someembodiments, such delivery might be advantageous, if for example, alongitudinal view of the artery is unobtainable or a faster treatmentparadigm is desirable. The transducers 8930, 8931 communicate with oneanother and are connected to a computer model of the region of interestbeing imaged (ROI), the ROI based on an MRI scan performed just prior tothe start of the procedure and throughout the procedure. Importantly,the transducers are placed posterior in the cross section of thepatient, an area with more direct access to the kidney region. The anglebetween the imaging transducers can be as low as 3 degrees or as greatas 180 degrees depending on the optimal position in the patient.

In another embodiment, an MRI is not performed but ultrasound isutilized to obtain all or part of the cross-sectional view in FIG. 19A.For example, 8930 might contain an imaging transducer as well as atherapeutic energy source (e.g. ionizing energy, HIFU, low energyfocused ultrasound, etc.) In some embodiments, a CT scan is utilized,which can obtain two dimensional images and output three dimensionalimages. In other embodiments, a fluoroscopy unit may be used.

FIG. 19B depicts an ultrasound image from a patient illustrating imagingof the region with patient properly positioned as described below. It isthis cross section that can be treated with image guided HIFU of therenal hilum region. The kidney 8935 is visualized in cross section andultrasound then travels through to the renal artery 8937 and vein 8941.The distance can be accurately measure 8943 with ultrasound (in thiscase 8 cm 8943). This information is useful to help model the deliveryof energy to the renal blood vessels. The blood vessels (vein and/orartery) are utilized as fiducials for the targeting of the ultrasound,and the kidney is used to verify that the vessels indeed are leading tothe correct organ. The kidney is further utilized to conduct theultrasound to the blood vessels.

FIGS. 19C-D depicts an actual treatment of the renal hilum 8945. Atargeting region 8946 is shown in which movement of the transducer andhilum is tracked and analyzed 8949 and 8948. The accuracy of thetracking is recorded and displayed 8948 over time. In this figure, thecool off period is shown and in FIG. 19D treatment 8954 is shown. Insome embodiments, energy is delivered in the manner described hereinthrough the kidney, which has been shown to be resilient to heat. Insome cases, movement of the renal hilum and the transducer are recordedin real time, and therapy of the blood vessels is depicted in real timeduring the treatment. Success of tracking may, as well as progress ofthe therapy at the time of treatment, may be presented on a screen forviewing by the user as shown in the tracking bar below the ultrasoundimage. Success may be considered when the targeting is maintained withinthe target circle 8647 at least 90% of the time of each treatment. Thistargeting accuracy is generally attributed to success in thepre-clinical studies described below. A motion tracking system is builtinto the system to ensure that a proper dose is delivered to the regionof the renal nerves leading to the kidney. The motion tracking systemrelates the coordinates in three dimensions to the treatment, and allowsfor the quality of the treatment to be determined. Therefore, in oneembodiment, focused energy is applied to the region of the blood vesselsto the kidney; hardware and software is utilized to quantify the degreeof movement between the treatment device and the treatment region; aquality factor is utilized to ascertain whether additional time needs tobe added to the treatment if the quality factor is too low to yield aneffective treatment.

FIGS. 19C-D depict the setup 8645 for the treatment of the renal bloodvessels along with actual treatment 8654 of the renal blood vessels8651. Window 8653 is the target window for the treatment. Although renalblood vessels are depicted, any blood vessel with a surrounding nervecan be targeted. Success factor 8648 is based on motion of the targetand/or operator. If the treatment fails to remain within the target 8647for a set period of time, then a failure indicator 8648 is shown on thescreen 8646 rather than a success indicator.

FIG. 19E depicts a clinical method based on the treatment shown in FIGS.19C-D above. The first step 8972 is to consider a delivery approach toapply ultrasound to nerves surrounding a blood vessel. The next step isto generate an ultrasound image of the region 8960 and the subsequentstep is to determine the distance 8962 to the blood vessel and thenintegrate the plan with the HIFU transducer 8964. Based on datagenerated above, parameters are determined to apply pulses, generallyless than 10 s of “on” time, to ramp the temperature of the regionaround the blood vessel to approximately 200 W/cm² in at least 2 seconds8970. The focus is then moved along the artery or blood vessel 8968 fromanterior to posterior and/or from side to side.

FIG. 20 depicts an alternative method, system 9000 and device to ablatethe renal nerves 9015 or the nerves leading to the renal nerves at theaorta-renal artery ostium 9010. The intravascular device 9020 is placedinto the aorta 9050 and advanced to the region of the renal arteries9025. Energy is applied from the transducer 9020 and focused 9040 (inthe case of HIFU, LIFU, ionizing radiation) to the region of the takeoffof the renal arteries 9025 from the aorta 9050. This intravascular 9030procedure can be guided using MRI and/or MRI thermometry or it can beguided using fluoroscopy, ultrasound, or MRI. Because the aorta islarger than the renal arteries, the HIFU catheter can be placed into theaorta directly and cooling catheters can be included as well. Inaddition, in other embodiments, non-focused ultrasound can be applied tothe region around the renal ostium or higher in the aorta. Non-focusedultrasound in some embodiments may require cooling of the tissuessurrounding the probe using one or more coolants but in someembodiments, the blood of the aorta will take the place of the coolant,by its high flow rate; HIFU, or focused ultrasound, may not need thecooling because the waves are by definition focused from differentangles to the region around the aorta. The vena cava and renal veins canalso be used as a conduit for the focused ultrasound transducer todeliver energy to the region as well. In one embodiment, the vena cavais accessed and vibratory energy is passed through the walls of the venacava and renal vein to the renal arteries, around which the nerves tothe kidney travel. The veins, having thinner walls, allow energy to passthrough more readily.

FIG. 21 a-b depicts an eyeball 9100. Also depicted are the zonules ofthe eye 9130 (the muscles which control lens shape) and ultrasoundtransducer 9120. The transducer 9120 applies focused ultrasound energyto the region surrounding the zonules, or the zonules themselves, inorder to tighten them such that a presbyopic patient can accommodate andvisualize object up close. Similarly, heat or vibration applied to theciliary muscles, which then increases the outflow of aqueous humor atthe region of interest so that the pressure within the eye cannot buildup to a high level. The ultrasound transducer 9120 can also be utilizedto deliver drug therapy to the region of the lens 9150, ciliary body,zonules, intra-vitreal cavity, anterior cavity 9140, posterior cavity,etc.

In some embodiments (FIG. 21 b), multiple transducers 9160 are utilizedto treat tissues deep within the eye; the ultrasonic transducers 9170are focused on the particular region of the eye from multiple directionsso that tissues along the path of the ultrasound are not damaged by theultrasound and the focus region and region of effect 9180 is theposition where the waves meet in the eye. In one embodiment, thetransducers are directed through the pars plana region of the eye totarget the macula 9180 at the posterior pole 9175 of the eye. Thisconfiguration might allow for heat, vibratory stimulation, drugdelivery, gene delivery, augmentation of laser or ionizing radiationtherapy, etc. In certain embodiments, focused ultrasound is not requiredand generic vibratory waves are transmitted through the eye atfrequencies from 20 kHz to 10 MHz. Such energy may be utilized to breakup clots in, for example, retinal venous or arterial occlusions whichare creating ischemia in the retina. This energy can be utilized incombination with drugs utilized specifically for breaking up clots inthe veins of the retina.

FIG. 22 depicts a peripheral joint 9200 being treated with heat and/orvibrational energy. Ultrasound transducer 9210 emits waves toward theknee joint to block nerves 9260 just underneath the bone periostium92209250 or underneath the cartilage. Although a knee joint is depicted,it should be understood that many joints can be treated including smalljoints in the hand, intervertebral joints, the hip, the ankle, thewrist, and the shoulder. Unfocused or focused ultrasonic energy can beapplied to the joint region to inhibit nerve function reversibly orirreversibly. Such inhibition of nerve function can be utilized to treatarthritis, post-operative pain, tendonitis, tumor pain, etc. In onepreferred embodiment, vibratory energy can be utilized rather than heat.Vibratory energy applied to the joint nerves can inhibit theirfunctioning such that the pain fibers are inhibited.

FIG. 23 a-b depicts closure of a fallopian tube 9300 of a uterus 9320using externally applied ultrasound 9310 so as to prevent pregnancy. MRIor preferably ultrasound can be utilized for the imaging modality.Thermometry can be utilized as well so as to see the true ablation zonein real time. The fallopian tube 9300 can be visualized usingultrasound, MRI, CT scan or a laparoscope. Once the fallopian tube istargeted, external energy 9310, for example, ultrasound, can be utilizedto close the fallopian tube to prevent pregnancy. When heat is appliedto the fallopian tube, the collagen in the walls are heated and willswell, the walls then contacting one another and closing the fallopianpreventing full ovulation and therefore preventing pregnancy. Althoughthere is no doppler signal in the fallopian tube, the technology forvisualization and treatment is similar to that for an artery or otherduct. That is, the walls of the tube are identified and modeled, thenfocused ultrasound is applied through the skin to the fallopian tube toapply heat to the walls of the lumen of the fallopian tube.

In FIG. 23 b, a method is depicted in which the fallopian tubes arevisualized 9340 using MRI, CT, or ultrasound. HIFU 9350 is applied undervisualization with MRI or ultrasound. As the fallopian tubes are heated,the collagen in the wall is heated until the walls of the fallopian tubeclose off. At this point the patient is sterilized 9360. During thetreating time, it may be required to determine how effective the heatingis progressing. If additional heat is required, then additional HIFU maybe added to the fallopian tubes until there is closure of the tube andthe patient is sterilized 9360. Such is one of the advantages of theexternal approach in which multiple treatments can be applied to thepatient, each treatment closing the fallopian tubes further, the degreeof success then assessed after each treatment. A further treatment canthen be applied 9370.

In other embodiments, ultrasound is applied to the uterus or fallopiantubes to aid in pregnancy by improving the receptivity of the spermand/or egg for one another. This augmentation of conception can beapplied to the sperm and egg outside of the womb as well, for example,in a test tube in the case of extra-uterine fertilization.

FIG. 24 depicts a feedback algorithm to treat the nerves of theautonomic nervous system. It is important that there be an assessment ofthe response to the treatment afterward. Therefore, in a first step,modulation of the renal nerves 9400 is accomplished by any or several ofthe embodiments discussed above. An assessment 9410 then ensues, theassessment determining the degree of treatment effect engendered; if acomplete or satisfactory response is determined 9420, then treatment iscompleted. For example, the assessment 9410 might include determinationthrough microneurography, assessment of the carotid sinus reactivity(described above), heart rate variability, measurement of norepinephrinelevels, tilt test, blood pressure, ambulatory blood pressuremeasurements, etc. With a satisfactory autonomic response, furthertreatment might not ensue or depending on the degree of response,additional treatments of the nerves 9430 may ensue.

FIG. 25 depicts a reconstruction of a patient from CT scan imagesshowing the position of the kidneys 9520 looking through the skin of apatient 9500. The ribs 9510 partially cover the kidney but do reveal awindow at the inferior pole 9530 of the kidney 9520. Analysis of many ofthese reconstructions has lead to clinical paradigm in which the ribs9510, pelvis 9420, and the vertebra 9440 are identified on a patient,the kidneys are identified via ultrasound and then renal arteries areidentified via Doppler ultrasound. A relevant clinical window may havean access angle of between 40 and 60 degrees.

As shown in FIG. 26 a, once the ribs and vertebra are identified withthe Doppler ultrasound, an external energy source 9600 can be applied tothe region. Specifically, focused ultrasound (HIFU or LIFU) can beapplied to the region once these structures are identified and a lesionapplied to the blood vessels (renal artery and renal nerve) 9620 leadingto the kidney 9610. As described herein, the position of the ultrasoundtransducer 9600 is optimized on the posterior of the patient as shown inFIG. 26A. That is, with the vertebra, the ribs, and the iliac crestbordering the region where ultrasound is applied.

Based on the data above and specifically the CT scan anatomicinformation in FIG. 26A, FIG. 26B depicts a device and system 9650designed for treatment of this region (blood vessels in the hilum of thekidney) in a patient. It contains a 0.5-3 Mhz ultrasound imagingtransducer 9675 in its center and a cutout or attachment location of theultrasound ceramic (e.g. PZT) for the diagnostic ultrasound placement.It also contains a movement mechanism 9660 to control the therapeutictransducer 9670. The diagnostic ultrasound device 9675 is coupled to thetherapeutic device in a well-defined, known relationship. Therelationship can be defined through rigid or semi-rigid coupling or itcan be defined by electrical coupling such as through infrared,optical-mechanical coupling and/or electro-mechanical coupling. Alongthe edges of the outer rim of the device, smaller transducers 9670 canbe placed which roughly identify tissues through which the ultrasoundtravels. For example, simple and inexpensive one or two-dimensionaltransducers might be used so as to determine the tissues through whichthe ultrasound passes on its way to the target can be used for thetargeting and safety. From a safety perspective, such data is importantso that the ultrasound does not hit bone or bowel and that thetransducer is properly placed to target the region around the renalblood vessels. Also included in the system is a cooling system totransfer heat from the transducer to fluid 9662 running through thesystem. Cooling via this mechanism allows for cooling of the ultrasoundtransducer as well as the skin beneath the system. A further feature ofthe system is a sensor mechanism 9665 which is coupled to the system9650 and records movement of the system 9650 relative to a baseline or acoordinate nearby. In one embodiment, a magnetic sensor is utilized inwhich the sensor can determine the orientation of the system relative toa magnetic sensor on the system. The sensor 9665 is rigidly coupled tothe movement mechanism 9660 and the imaging transducer 9675. In additionto magnetic, the sensor might be optoelectric, acoustic, imaging (e.g.camera), or radiofrequency based.

Furthermore, the face 9672 of the transducer 9670 is shaped such that isfits within the bony region described and depicted in FIG. 26A. Forexample, in some embodiments, the shape might be elliptical or aspheric;in other embodiments, the shape may be triangular or pie shaped. Inaddition, in some embodiments, the ultrasound imaging engine might notbe directly in the center of the device and in fact might be superior tothe center and closer to the superior border of the face and closer tothe ribs, wherein the renal artery is visualized better with the imagingprobe 9675.

Given the clinical data as well as the devised technologies describedabove (e.g. FIG. 26A-B), FIG. 27 illustrates the novel treatment plan9700 to apply energy to the nerves around the renal artery with energydelivered from a position external to the patient.

In one embodiment, the patient is stabilized and/or positioned such thatthe renal artery and kidneys are optimally located 9710. Diagnosticultrasound 9730 is applied to the region and optionally, ultrasound isapplied from a second direction 9715. The positioning and imagingmaneuvers allow the establishment of the location of the renal artery,the hilum, and the vein 9720. A test dose of therapeutic energy 9740 canbe applied to the renal hilum region. In some embodiments, temperature9735 can be measured. This test dose can be considered a full dose ifthe treatment is in fact effective by one or more measures. Thesemeasures might be blood pressure 9770, decrease in sympathetic outflow(as measured by microneurography 9765), increase in parasympatheticoutflow, change in the caliber of the blood vessel 9755 or a decrease inthe number of spontaneous spikes in a microneurographic analysis in aperipheral nerve (e.g. peroneal nerve) 9765, or an MRI or CT scan whichreveals a change in the nervous anatomy 9760. In some embodiments,indices within the kidney are utilized for feedback. For example, theresistive index, a measure of the vasoconstriction in the kidneymeasured by doppler ultrasound is a useful index related to the renalnerve activity; for example, when there is greater autonomic activity,the resistive index increases, and vice versa.

Completion of the treatment 9745 might occur when the blood pressurereaches a target value 9770. In fact, this might never occur or it mayoccur only after several years of treatment. The blood pressure mightcontinually be too high and multiple treatments may be applied over aperiod of years . . . the concept of dose fractionation. Fractionationis a major advantage of applying energy from a region external to aregion around the renal arteries in the patient as it is more convenientand less expensive when compared to invasive treatments such asstimulator implantation and interventional procedures such ascatheterization of the renal artery.

Another important component is the establishment of the location andposition of the renal artery, renal vein, and hilum of the kidney 9720.As discussed above, the utilization of Doppler ultrasound signalingallows for the position of the nerves to be well approximated such thatthe ultrasound can be applied to the general region of the nerves. Theregion of the nerves can be seen in FIGS. 29A-D. FIGS. 29A-C aresketches from actual histologic slices. The distances from the arterialwall can be seen at different locations and generally range from 0.3 mmto 10 mm. Nonetheless, these images are from actual renal arteries andnerves and are used so as to develop the treatment plan for the system.For example, once the arterial wall is localized 9730 using the Doppleror other ultrasound signal, a model of the position of the nerves can beestablished and the energy then targeted to that region to inhibit theactivity of the nerves 9720. Notably, the distance of many of thesenerves from the wall of the blood vessel indicate that a therapy whichapplies radiofrequency to the wall of the vessel from the inside of thevessel likely has great difficulty in reaching a majority of the nervesaround the blood vessel wall.

For example, FIG. 29D depicts a schematic from a live human ultrasound.As can be seen, the ultrasound travels through skin, through thesubcutaneous fat, through the muscle and at least partially through thekidney 8935 to reach the hilum 8941 of the kidney and the renal bloodvessels 8937. This direction was optimized through clinicalexperimentation so as to not include structures which tend to scatterultrasound such as bone and lung. Experimentation lead to theoptimization of this position for the imaging and therapy of the renalnerves. The position of the ultrasound is between the palpable bonylandmarks on the posterior of the patient as described above and below.The vertebrae are medial, the ribs superior and the iliac crestinferior. Importantly, the distance of these structures 8943 isapproximately 8-12 cm and not prohibitive from a technical standpoint.These images from the ultrasound are therefore consistent with theresults from the CT scans descrbied above as well.

FIG. 29E depicts the surface area 8760 available to an ultrasoundtransducer for two patients out of a clinical study. One patient wasobese and the other thinner. Quantification of this surface area 8762was obtained by the following methodology: 1) obtain CT scan; 2) markoff boundary of organs such as the vertebrae, iliac crest, and ribs; 3)draw line from renal blood vessels to the point along the edge of thebone; 4) draw perpendicular from edge bone to the surface of the skin;5) map the collection of points obtained along the border of the bone.The surface area is the surface area between the points and the maximumdiameter is the greatest distance between the bony borders. Thecollection of points obtained with this method delimits the area on theposterior of the patient which is available to the ultrasound transducerto either visualize or treat the region of the focal spot. By studying aseries of patients, the range of surface areas was determined so as toassist in the design which will serve the majority of patients. Thetransducers modeled in FIG. 30 have surface areas of approximately 11×8cm or 88 cm² which is well within the surface area 8762 shown in FIG.29E, which is representative of a patient series. Furthermore thelength, or distance, from the renal artery to the skin was quantified inshortest ray 8764 and longest ray 8766. Along with the angular datapresented above, these data enable design of an appropriate transducerto achieve autonomic modulation and control of blood pressure.

In a separate study, it was shown that these nerves could be inhibitedusing ultrasound applied externally with the parameters and devicesdescribed herein. Pathologic analysis revealed that the nerves aroundthe artery were completely inhibited and degenerated, confirming theability of the treatment plan to inhibit these nerves and ultimately totreat diseases such as hypertension. Furthermore, utilizing theseparameters, did not cause any damage within the path of the ultrasoundthrough the kidney and to the renal hilum.

Importantly, it has also been discovered via clinical trials that whenultrasound is used as the energy applied externally, that centering thediagnostic ultrasound probe such that a cross section of the kidney isvisualized and the vessels are visualized, is an important component ofdelivering the therapy to the correct position along the blood vessels.One of the first steps in the algorithm 9700 is to stabilize the patientin a patient stabilizer custom built to deliver energy to the region ofthe renal arteries. After stabilization of the patient, diagnosticultrasound is applied to the region 9730 to establish the extent of theribs, vertebrae, and pelvis location. Palpation of the bony landmarksalso allows for the demarcation of the treatment zone of interest. Theexternal ultrasound system is then placed within these regions so as toavoid bone. Then, by ensuring that a portion of the external energy isdelivered across the kidney (for example, using ultrasound forvisualization), the possibility of hitting bowel is all but eliminated.The ultrasound image in FIG. 29D depicts a soft tissue path from outsidethe patient to the renal hilum inside the patient. The distance isapproximately 8-16 cm. Once the patient is positioned, a cushion 9815 isplaced under the patient. In one embodiment, the cushion 9815 is simplya way to prop up the back of the patient. In another embodiment, thecushion 9815 is an expandable device in which expansion of the device isadjustable for the individual patient. The expandable component 9815allows for compression of the retroperitoneum (where the kidney resides)to slow down or dampen movement of the kidney and maintain its positionfor treatment with the energy source or ultrasound.

A test dose of energy 9740 can be given to the region of the kidneyhilum or renal artery and temperature imaging 9735, constriction ofblood vessels 9755, CT scans 9760, microneurography 9765 patch orelectrode, and even blood pressure 9770. Thereafter, the treatment canbe completed 9745. Completion might occur minutes, hours, days, or yearslater depending on the parameter being measured.

Through experimentation, it has been determined that the region of therenal hilum and kidneys can be stabilized utilizing gravity with localapplication of force to the region of the abdomen below the ribs andabove the renal pelvis. For example, FIGS. 28A-C depict examples ofpatient positioners intended to treat the region of the renal bloodvessels.

FIG. 28A is one example of a patient positioned in which the ultrasounddiagnostic and therapeutic 9820 is placed underneath the patient. Thepositioner 9810 is in the form of a tiltable bed. A patient elevator9815 placed under the patient pushes the renal hilum closer to the skinand can be pushed forward in this manner; as determined in clinicaltrials, the renal artery is approximately 2-3 cm more superficial inthis type of arrangement with a range of approximately 7-15 cm in thepatients studied within the clinical trial. The weight of the patientallows for some stabilization of the respiratory motion which wouldotherwise occur; the patient elevator can be localized to one side oranother depending on the region to be treated. Alternative approaches(in the case where the physician wants to maintain the patient in a flatposition) are to place a positioning device under the patient's legs andmaintain the upper torso substantially flat.

FIG. 28B detects a more detailed configuration of the ultrasound imagingand therapy engine 9820 inset. A patient interface 9815 is utilized tocreate a smooth transition for the ultrasound waves to travel throughthe skin and to the kidneys for treatment. The interface is adjustablesuch that it is customizable for each patient.

FIG. 28C depicts another embodiment of a positioner device 9850, thistime meant for the patient to be face down. In this embodiment, thepatient is positioned in the prone position lying over the patientelevator 9815. Again, through clinical experimentation, it wasdetermined that the prone position with the positioner under the patientpushes the renal hilum posterior and stretches out the renal artery andvein allowing them to be more visible to ultrasound and accessible toenergy deposition in the region. The positioner underneath the patientmight be an expandable bladder with one or more compartments whichallows for adjustability in the amount of pressure applied to theunderside of the patient. The positioner might also have a back sidewhich is expandable 9825 and can push against the posterior side of thepatient toward the expandable front side of the positioner therebycompressing the stretched out renal blood vessels to allow for a moresuperficial and easier application of the energy device. These data canbe seen in FIGS. 7G and 7H where the renal artery is quite a bit closerto the skin (7-17 cm down to 6-10 cm). The position of the energydevices for the left side 9827 of the patient and right side 9828 of thepatient are depicted in FIG. 28C. The ribs 9829 delimit the upper regionof the device placement and the iliac crest 9831 delimits the lowerregion of the device placement. The spinous processes 9832 delimit themedial edge of the region where the device can be placed and the regionbetween 9828 is the location where the therapeutic transducer is placed.

FIGS. 28D-28E depict a system implementation of the description above.Belt 9853 is fixed to the transducer 9855. Bladder 9857 is an adaptableand fillable cavity which can be used to help stabilize the flank regionof the patient by pressing the posterior skin against the belt andtransducer 9855. The transducer incorporates many of the embodimentsdescribed herein. For example, in the illustrated embodiments, thetransducer is designed and manufactured with such a specification thatit applies energy directed to the region of the renal artery and nerves.The transducer may be shaped like a pizza slice with annular components,or multiple elements forming into a global shape, like a pizza slice (asdescribed herein). The transducer may also provide imaging and motiontracking capability such as with a pulse-echo detection system or withintegral ultrasound imaging. The imaging aid might detect an indwellingvascular catheter or an implant. Nonetheless, the imaging aid can bothdetect the target track its motion. The therapeutic aspect of thetransducer 9855 may generate focused ultrasound at a frequency of 0.5MHz to 3 MHz depending on the specific configuration or pattern desired.Monitor 9862 is utilized to monitor the progress of the therapythroughout the treatment regimen.

Thus, in one embodiment of the system, as depicted in FIGS. 28D and 28E,the system comprises a belt which circumscribes the patient and appliesa bladder (optionally) on one side of the patient to limit excursion ofthe abdominal organs and at least partially stabilize the abdominalorgans, such as the kidney. Additionally, imaging and tracking may beutilized to maintain the positioning of the therapeutic energy focus.The stabilized focused energy system can then be automatically directed(e.g., by a processor) to track and follow the blood vessels and carryout a treatment according to a treatment plan, e.g., to treat tissue(nerves) surround the vessels leading to the kidney. The bladders may befilled automatically. In some cases, motion controllers may be utilizedto direct the therapeutic energy focus to regions close to or within thehilum of the kidney.

FIGS. 28E-G depict a more complete picture of the transducer to beapplied to the back of the patient 9855 within the belt 9853 FIG. 28Fdepicts a 6 dimensional movement mechanism for the transducer platformwith a positionable arm and its fit into the system configuration 9860.Six degrees of freedom are available for movement, which includesrotation and translation of the transducer. The platform is able to movein 6 degrees of freedom and the bottom mover allows for the transducerto be pressed against the skin of the patient.

FIG. 28H depicts a patient treatment system 9800 in which a catheter9805 is inserted into the patient 9810 and the system 9820 is placedbehind the patient. Coupling applicator 9815 is pressed against thepatient to maintain coupling contact between the therapeutic system 9820and the patient. Catheter 9805 can be utilized to assist in targeting ofthe blood vessels and nerves being treated by the therapeutic system.Maintaining the therapeutic system behind the patient 9820 allows thepatient's weight to be utilized in maintaining coupling between thesystem 9820 and patient 9810.

FIG. 28I is a close up picture of the transducer 9820. Elements 9809 aredepicted with different phasings patterns to meet at the intersection9807. Elements 9809 can also translate or rotate within the transducerallowing for a multi-modality.

FIG. 28J depicts a component 9865 to apply pressure to specific anatomicregions of the patient. Individual bladders 9860 can be inflated 9860 ordeflated 9863 depending on the region of the patient for which pressureis applied. Such a system aids with conforming the applicator to thepatient. In FIG. 28K, another configuration of a system to applytherapeutic energy to the region of the renal hilum is depicted.Transducer 9875 is depicted on the portion of the table which ispositioned under the patient to be treated. Angiogram 9874 is visible inthe case where a catheter is utilized for targeting. Therefore in oneembodiment, the system to apply energy to the renal artery region isdescribed in which a typical OR or cath lab table is retrofitted for atherapeutic ultrasound underneath the patient. The therapeuticultrasound array contains a movement mechanism to maintain the array incontact with the skin of the patient, wherein the mechanism is able totranslate to the left side of the patient or the right side of thepatient. The movement mechanism can operate (e.g., to track a target)based on an image (e.g., a doppler image) of a blood vessel.

FIG. 28K depicts the movement mechanism 9875 within a table 9870 totreat a patient who is positioned in the supine position. The tableelevation is on the front side of the patient, pushing upward toward therenal hilum and kidneys. The head of the table may be dropped orelevated so as to allow specific positioning positions. The elevatedportion may contain an inflateable structure which controllably appliespressure to one side or another of the torso, head, or pelvis of thepatient.

FIG. 29A-C depicts the anatomical basis 9900 of the targeting approachdescribed herein. These figures are derived directly from histologicslides. Nerves 9910 can be seen in a position around renal artery 9920and vein 9922. The range of radial distance from the artery is out to 2mm and even out to 10 mm. Anatomic correlation with the modeling in FIG.16B reveals the feasibility of the targeting and validates the approachbased on actual pathology; that is, the approach of applying therapy tothe renal nerves by targeting the adventitia of the artery, and usingthe kidney as both a conduit and fiducial for the focused energy (e.g.,focused ultrasound energy). This is important because the methodologyused to target the nerves is one of detecting the Doppler signal fromthe artery and then targeting the vessel wall around the doppler signal.Nerves 9910 can be seen surrounding the renal artery 9920 which putsthem squarely into the temperature field shown in 16B indicating thefeasibility of the outlined targeting approach in FIG. 27 and the lesionconfiguration in FIG. 16A. Further experimentation (utilizing similartypes of pathology as well as levels of norepinephrine in the kidney)reveals that the required dose of ultrasound to the region to affectchanges in the nerves is on the order of 100 W/cm² for partialinhibition of the nerves and 1-2 kW/cm² for complete inhibition andnecrosis of the nerves. These doses or doses in between them might bechosen depending on the degree of nerve inhibition desired in thetreatment plan. Importantly, it was further discovered through theexperimentation that an acoustic plane through the blood vessels wasadequate to partially or completely inhibit the nerves in the region.That is to say, that a plane through which the blood vessels travelsperpendicularly is adequate to ablate the nerves around the artery asillustrated in FIG. 16B. Until this experimentation, there had been noevidence that ultrasound would be able to inhibit nerves surrounding anartery by applying a plane of ultrasound through the blood vessel.Indeed, it was proven that a plane of ultrasound essentially couldcircumferentially inhibit the nerves around the blood vessel.

FIG. 29D depicts a treatment combining the technical factors describedherein. An ultrasound image with a doppler is shown with a blood vessel8941 leading to a kidney 8935. The blood vessel (doppler signal andimage) is targeted 8937 in three dimensions and the kidney 8935 is usedas a conduit to conduct the focused energy (in this case ultrasound)toward the blood vessel. The kidney is further used as a fiducial, whichindicates the direction, and indicates that the correct vessel is indeedtargeted. A treatment paradigm is created in which a program isgenerated to move the focal plane around the target in three dimensions.Data generated, both theoretically and in pre-clinical models, revealsthat the kidney indeed can be used as a conduit to conduct HIFU energybecause the ability of the kidney to transmit ultrasound without heatingis outstanding due to its high blood flow. Therefore, one preferredembodiment is that the kidney is utilized as a fiducial to direct thefocused ultrasound, as well as allowing transmission through to theblood vessels of the kidney.

FIGS. 30A-I depict three dimensional simulations from a set of CT scansfrom the patient model shown in FIG. 26A. Numerical simulations wereperformed in three dimensions with actual human anatomy from the CTscans. The same CT scans utilized to produce FIGS. 7E, 19, and 25 wereutilized to simulate a theoretical treatment of the renal artery regionconsidering the anatomy of a real patient. Utilizing the doses shown inthe experimentation above (FIGS. 29A-D) combined with the human anatomyfrom the CT scans, it is shown with these simulations that the abilityexists to apply therapeutic ultrasound to the renal hilum from aposition outside the patient. In combination with FIG. 29, which asdiscussed, depicts the position of the nerves around the blood vesselsas well as the position of the vessels in an ultrasound, FIG. 30A-Idepicts the feasibility of an ultrasound transducer which is configuredto apply the required energy to the region of the hilum of the kidneywithout damaging intervening structures. These simulations are in factconfirmation for the proof of concept for this therapy and incorporatethe knowledge obtained from the pathology, human CT scans, humanultrasound scans, and the system designs presented previously above.

In one embodiment, FIG. 30A, the maximum intensity is reached at thefocus 10010 is approximately 186 W/cm² with a transducer 10000 design at750 MHz; the transducer is approximately 11×8 cm with a central portion10050 for an ultrasound imaging engine. The input wattage to thetransducer is approximately 120 W-150 W depending on the specificpatient anatomy. The input voltage might be as high as 1000 W dependingon the desired peak intensity at the focus. For example, for a peakintensity of 2 kW/cm², it may be desirable to have an input wattage ofapproximately 600-800 W.

FIGS. 30B and 30C depict the acoustic focus 10020, 10030 at a depth ofapproximately 9-11 cm and in two dimensions. Importantly, the region(tissues such as kidney, ureter, skin, muscle) proximal (10040 and10041) to the focus 10020, 10030 do not have any significant acousticpower absorption indicating that the treatment can be applied safely tothe renal artery region through these tissues as described above.Importantly, the intervening tissues are not injured in this simulationindicating the feasibility of this treatment paradigm.

FIGS. 30D-F depict a simulation with a transducer 10055 having afrequency of approximately 1 MHz. With this frequency, the focal spot10070, 10040, 10050 size is a bit smaller (approximately 2 cm by 0.5 cm)and the maximum power higher at the focus, approximately 400 W/cm² thanshown in FIGS. 30A-C. In the human simulation, this is close to anoptimal response and dictates the design parameters for the externallyplaced devices. The transducer in this design is a rectangular type ofdesign (spherical with the edges shaved off) so as to optimize theworking space in between the posterior ribs of the patient and thesuperior portion of the iliac crest of the patient. Its size isapproximately 11 cm×8 cm which as described above and below is wellwithin the space between the bony landmarks of the back of the patient.

FIGS. 30G-I depict a simulation with similar ultrasound variables asseen in FIGS. 30D-F. The difference is that the transducer 10090 wasleft as spherical with a central cutout rather than rectangular with acentral cutout. The spherical transducer setup 10090 allows for agreater concentration of energy at the focus 1075 due to the increasedsurface area of vibratory energy. Indeed, the maximum energy from thistransducer (FIG. 30G) is approximately 744 W/cm² whereas for thetransducer in FIG. 30 d, the maximum intensity is approximately 370W/cm². FIG. 30H depicts one plane of the model and 30I another plane.Focus 10080, 10085 is depicted with intervening regions 10082 and 10083free from acoustic power and heat generation, similar to FIG. 30A-F.

These simulations confirm the feasibility of a therapeutic treatment ofthe renal sympathetic nerves from the outside without damage tointervening tissues or structures such as bone, bowel, and lung.Hypertension is one clinical application of this therapy. A transducerwith an imaging unit within is utilized to apply focused ultrasound to arenal nerve surrounding a renal artery. Both the afferent nerves andefferent nerves are affected by this therapy.

Other transducer configurations are possible. Although a singletherapeutic transducer is shown in FIG. 30A-I, configurations such asphased array therapy transducers (more than one independently controlledtherapeutic transducer) are possible. Such transducers allow morespecific tailoring to the individual patient. For example, a largertransducer might be utilized with 2, 3, 4 or greater than 4 transducers.Individual transducers might be turned on or off depending on thepatients anatomy. For example, a transducer which would cover a rib inan individual patient might be turned off during the therapy.

Although the central space is shown in the center of the transducer inFIGS. 30A-I, the imaging transducer might be placed anywhere within thefield as long as its position is well known relative to the therapytransducers. For example, insofar as the transducer for therapy iscoupled to the imaging transducer spatially in three dimensional spaceand this relationship is always known, the imaging transducer can be inany orientation relative to the therapeutic transducer.

Another embodiment of a customized transducer 11030 is depicted in FIGS.30J-30K. Importantly, this transducer is specifically designed toaccommodate the anatomy shown above for the kidney anatomy. The pizzaslice shape 11000 is unique to treat the anatomy in which the ribs,spine and pelvis are considered. Sensors 11040 are located along theedges of the transducer and allow for imaging or otherwise to detect thedirection of the ultrasound system as it travels through the patienttoward its target. At the tip of the system, 11050, an ultrasoundimaging probe is included where the probe is coupled to the therapeuticultrasound array 11030 and 11020. The number of elements 11030determines the spatial resolution of the array and the degree to whichthe focus can be electronically controlled.

The sensors around the side 11040 may be small 1D imaging transducers orcontain a single plane. Alternatively, they may be acoustic time offlight sensors for measuring the distance to the target or a combinationof the two different techniques.

FIGS. 30L-N depicts additional views of the transducer in which theimaging component is in the center 11070, side cutout 11075, and withinthe pie slice shape 11085. The pizza slice shape does not necessarilyhave to be shaped as a slice but might be a larger array in which aslice shape is produced by turning on or off any number of transducers.The transducers in such an embodiment can have square, annular, orrectangular elements each of which has its own controller for imaging ortherapeutic uses.

FIG. 30O-Q depicts a transducer with several elements arranged into afixed focus 11130. Each of the 6 elements 11150 can be tuned to focus ona spot a given focal length from the transducer. The pizza slice shapecan be fit into the region between the ribs and spine and the pelvis toapply therapy to a blood vessel such as the renal artery or the renalvein. FIG. 30Q depicts discreet movers 11141, 11143, 11145 which dictatethe degree of overlap at the focus 11147.

FIG. 30R-S depicts a transducer 11200 with many elements 11230. Again,although shaped like a slice of a pie 11220, the shape can be created byturning on transducers from a larger cutout. A cross section 11210 isshown as well (FIG. 30R) revealing a thickness of the array which canrange from several mm to a few cm. The profile is produced such that thetransducer can be adapted to fit into the acoustic window of a humanpatient with anatomy described herein.

FIG. 30V is an expanded version of a transducer 11300 in which discretebowls are fit together to simulate a larger bowl 11310 approximation. Inthis arrangement, the individual bowls 11324, 11324, 11326 each providea piece of the curvature of a larger bowl, which would otherwise be verydifficult to manufacture.

FIG. 30W depicts the assembly of the configuration 11350 with the bowlsin combination which when powered, creates a single focus 11355. Bymoving each individual bowl slightly, the focus can be made to beelongate or circular.

FIGS. 30T-U depict simulations of the annular array transducers shown inFIGS. 30J-K. The simulation reveals that the focus can be electronicallycontrolled between less than 10 cm distance 11510 to greater than 14 cm11500. These distances are compatible with the blood vessels leading tothe kidney and are delivered from within the envelope of the window onthe posterior portion of the patient's back.

FIG. 30V depicts an exploded view of an assembly of a transducer 11300.A base 11310 might contain a motion control system for x-y-z motion, andoptionally a pivot for rotation of the ultrasound array. Array 11322 iscomprised of one or more ultrasound emanating crystals 11324 withdifferent curvatures 11326, 11320 to focus energy. Housing 11330 mightcontain a nosecone or other directional structure to direct theultrasound energy to a focus. Covering 11340 is a coupling structurewith an integral membrane to couple the ultrasound energy to thepatient. The transducer 11322 might provide a combination of phasing andmechanical movement for its operation.

FIG. 31A depicts a perspective view of a transducer device customizedfor the anatomy of the blood vessels leading to the kidney. This designis based on the anatomic, biologic, and technical issues discovered anddescribed above specific for the clinical treatment of nervessurrounding the blood vessels which go to the kidney. Transducer 11650has multiple elements and is also able to be pivoted and translated. Theindividual elements of the array can be phased so that different depthsof foci can be achieved 11600, 11610 to treat regions around a bloodvessel 11620. An imaging transducer 11710 is attached to, or integratedwith, the device 11700. Although the ultrasound imaging transducer hasbeen described, in other embodiments, MRI, CT, or fluoroscopy can alsobe linked to the system 11700. The device further contains elementsdescribed above such as a mover to move the entire device as a completeunit, motion tracking to track its global motion in three dimensionalspace, and a water circulation system to maintain the temperature of theskin and the transducer to acceptable levels.

Angle 11652 is important to the anatomy which is being treated. Itrepresents the envelope of the therapeutic beam and is incorporated intothe design of the system. It is represented in one plane in this figureand would cover approximately 40 to 70 degrees in this figure whichallows for a treatment depth of between 6 cm and 15 cm. For the shortdimension (into the drawing), the angle (not shown) would be 35 to 65degrees. The treatment depth may be desirably adjusted with differentphasing from the transducer; however, the shape of the focus is notsubstantially affected. The position in X and Y may be adjusted usingmechanical manipulation but can also be adjusted via phasing elements.Therefore, in one embodiment, an ultrasound transducer is describedwithin which a multi-element array is disposed, the transducer devisedto allow for electrical focusing of a focused ultrasound beam at anangle 11652 to the central axis of the transducer to move the beam focusin the direction perpendicular to the plane of the transducer but at anangle to the central axis of the transducer. The angle is customized forthe anatomy being treated. For example, when treating a region such asthe renal artery and nerve going to the kidney, the blood vessels arelocated at an angle from a plane of the skin when the transducer isplace between the ribs, iliac crest, and spine (for example, see FIG.31A, angle 11652, transducer 11650 is placed on the skin underneath theribs, lateral to the spine and superior to the iliac crest). A mover mayalso be provided, which moves the transducer in the plane of thetransducer and perpendicular to the central axis of the transducer.

FIG. 31B depicts another embodiment of a transducer 11700 designed todeliver focused ultrasound specifically to the region of the kidney andassociated blood vessels 11770. The transducer has multiple small bowlshaped transducers 11720 fitted together for a deep focus 11740 of theultrasound. The smaller bowl transducers 11720 are each movableutilizing a mechanical manipulator 11780 so as to create foci withdifferent sizes at the target. A water cooling system is present as well11730, which ensures that the skin and the transducers are maintained ata predetermined temperature. The variations in foci include elongated,spiral, and annular, each with different depths 11740. In thisembodiment, imaging is a component of the transducers 11720. ATOF(acoustic time of flight) receivers 11710 can optionally receive signalsfrom transducers 11750 on an indwelling vascular catheter 11760, whichcontains piezoelectric transducers capable of transmitting informationthrough the patient to receivers 11710.

FIG. 31C depicts a two component mover mechanism (termed upper and lowermovers) 11820 with a patient table 11800 to house the transducerarrangement and hold a patient. A mover 11850 is responsible for placingthe transducer 11840 against the skin of the patient inside of thecutout 11830 in the table; clinical studies have shown that up to 50pounds of pressure can be applied by the lower transducer to the skin ofthe patient to maintain coupling. The mover 11850 is also responsiblefor lowering the upper transducer 11840. The upper transducer 11840 ispositioned at the angle and position required to treat a region such asthe renal nerves around a renal blood vessel. Electronic focusing mightbe utilized for some components of the system, including the z directionwhich is the vertical direction through the central axis of thetransducer and would generally be pointing in the direction in and outof the patient being treated. With electronic focusing, the distance canbe automatically determined and calibrated relative to the transducer.In some embodiments, X and Y motions are altered electronically withvarious phasing patterns created through the transducer. In someembodiments, a combination of electronic phasing and mechanical movementis utilized to achieve the proper focusing and positioning of the systemon the patient. The transducers being used for the therapeuticapplication of energy to the patient might also be utilized fordetection of ultrasound signals which can be used for imaging detection.A separate imaging transducer can be utilized to augment the therapytransducer. For example, acoustic time of flight can be utilized or Bmode or Doppler imaging can be utilized. Therefore, in one embodiment,the transducer is positioned at the proper angle to reach the renalblood vessels

FIG. 31D depicts a system and subsystem overview of one configuration. Atransducer belt 12010 can be applied to a patient, wherein the beltincludes an applicator 12020 with transducer containing a membraneassembly, packaging, temperature sensors, and coupling attachments forcoupling to the skin of the patient. Within the transducer assembly is acarveout for an imaging engine 12180, which can be an annular array forimaging in the same package as the therapy transducer, or it can be aseparate array 12040 tuned for a different frequency specific forimaging. Within the transducer belt is a mover for the applicator, forexample, a mover 12030 which can translate in X-Y-Z and rotate around apivot to deliver an ultrasound focus to any position within a spacearound a blood vessel. Alternatively, in another embodiment, phasedarray transducers may be utilized in for treatment, imaging, or both. Acooling subsystem 12060 is a component of the system, wherein thecooling subsystem is configured to maintain the transducer and membranetemperature at a pre-specified level. An optional targeting catheter12170 is included in the system, wherein the targeting catheter may beused in characterizing the energy being delivered from the focusedultrasound as well as in assisting and verifying the targeting accuracyof the imaging and the coupling of the imaging to the motion control12030. The targeting catheter can also include sensors to determine theamount of energy applied to the vessel, the temperature of the vesseland surroundings, the acoustic power flux, and the degree of motion ofthe vessel during, before, or after treatment. A user interface is alsoincluded, the user interface comprising a track ball, a mouse, a touchscreen, or a keyboard to allow user interaction with the system. Thesystem is powered using power supplies 12150 which can be switched ornon-switched depending on which subsystem is being activated at anygiven time.

FIGS. 30R and 30S depict the active shape of the transducer, and 30T and30U depict the simulation of the focused ultrasound at the depth oftreatment. The perspective view of the focus 11600 is shown in FIG. 31Aand the annular transducer 11650 which delivers the ultrasound to ablood vessel 11620 and surrounding nerves 11610 is shown as well. Animaging array 11710 is included in the system 11700 as well.

1. A method to apply a nerve inhibiting cloud surrounding a bloodvessel, comprising: creating a treatment plan, wherein the treatmentplan prescribes application of the nerve inhibiting cloud towards atleast a majority portion of a circumference of a blood vessel wall; andapplying the nerve inhibiting cloud towards the majority portion of thecircumference of the blood vessel wall for a time sufficient to inhibita function of a nerve that surrounds the blood vessel wall. 2-19.(canceled)